Sweet flavor modifier

ABSTRACT

The present invention includes compounds having structural formula (I), or pharmaceutically acceptable salts, solvate, and/or ester thereof. These compounds are useful as sweet flavor modifiers. The present invention also includes compositions comprising the present compounds and methods of enhancing the sweet taste of ingestible compositions. Furthermore, the present invention provides methods for preparing the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/731,224, which is a division of U.S. application Ser. No. 14/061,013,filed Oct. 23, 2013, now U.S. Pat. No. 9,049,878, which is acontinuation of U.S. application Ser. No. 13/076,632, filed Mar. 31,2011, now U.S. Pat. No. 8,592,592, which claims the benefit of priorityto U.S. Provisional Patent Application No. 61/320,528, filed Apr. 2,2010 and entitled “SWEET FLAVOR MODIFIER”; and U.S. Provisional PatentApplication No. 61/422,341, filed Dec. 13, 2010 and entitled “SWEETFLAVOR MODIFIER”. The contents of these applications are herebyincorporated by reference in their entireties for all purposes.

FILED OF THE INVENTION

The invention relates to compounds useful as sweet flavor modifiersand/or tastants.

BACKGROUND OF THE INVENTION

The taste system provides sensory information about the chemicalcomposition of the external world. Taste transduction is one of the mostsophisticated forms of chemical-triggered sensation in animals.Signaling of taste is found throughout the animal kingdom, from simplemetazoans to the most complex of vertebrates. Mammals are believed tohave five basic taste modalities: sweet, bitter, sour, salty, and umami(the taste of monosodium glutamate, a.k.a. savory taste).

Obesity, diabetes, and cardiovascular disease are health concerns on therise globally, but are growing at alarming rates in the United States.Sugar and calories are key components that can be limited to render apositive nutritional effect on health. High-intensity sweeteners canprovide the sweetness of sugar, with various taste qualities. Becausethey are many times sweeter than sugar, much less of the sweetener isrequired to replace the sugar.

High-intensity sweeteners have a wide range of chemically distinctstructures and hence possess varying properties, such as, withoutlimitation, odor, flavor, mouthfeel, and aftertaste. These properties,particularly flavor and aftertaste, are well known to vary over the timeof tasting, such that each temporal profile is sweetener-specific(Tunaley, A., “Perceptual Characteristics of Sweeteners”, Progress inSweeteners, T. H. Grenby, Ed. Elsevier Applied Science, 1989).

Sweeteners such as saccharin and6-methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium salt(acesulfame potassium) are commonly characterized as having bitterand/or metallic aftertastes. Products prepared with 2,4-dihydroxybenzoicacid are claimed to display reduced undesirable aftertastes associatedwith sweeteners, and do so at concentrations below those concentrationsat which their own tastes are perceptible. Also, high intensitysweeteners such as sucralose and aspartame are reported to havesweetness delivery problems, i.e., delayed onset and lingering ofsweetness (S. G. Wiet, et al., J. Food Sci., 58(3):599-602, 666 (1993)).

It has been reported that an extra-cellular domain, e.g., the Venusflytrap domain of a chemosensory receptor, especially one or moreinteracting sites within the Venus flytrap domain, is a suitable targetfor compounds or other entities to modulate the chemosensory receptorand/or its ligands. Certain compounds have been reported to havesuperior sweet taste enhancing properties and are described in the fourpatent applications listed below.

(1) U.S. patent application Ser. No. 11/760,592, entitled “Modulation ofChemosensory Receptors and Ligands Associated Therewith”, filed Jun. 8,2007; (2) U.S. patent application Ser. No. 11/836,074, entitled“Modulation of Chemosensory Receptors and Ligands Associated Therewith”,filed Aug. 8, 2007; (3) U.S. Patent Application Ser. No. 61/027,410,entitled “Modulation of Chemosensory Receptors and Ligands AssociatedTherewith”, filed Feb. 8, 2008; and (4) International Application No.PCT/US2008/065650, entitled “Modulation of Chemosensory Receptors andLigands Associated Therewith”, filed Jun. 3, 2008. The content of theseapplications are herein incorporated by reference in their entirety forall purposes.

The present invention provides novel and inventive sweet taste enhancerswith desirable characteristics.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a compound havingstructural Formula (I) or (I′):

or a tautomer, salt, and/or solvate, wherein: A is —OR¹, —NR¹C(O)R²,—NHOR¹, —NR¹R², —NR¹CO₂R², —NR¹C(O)NR²R³, —NR¹C(S)NR²R³ or—NR¹C(═NH)NR²R³; B is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, acyl, substitutedacyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR⁴,—S(O)_(a)R⁴, —NR⁴R⁵, —C(O)NR⁴R⁵, —CO₂R⁴, —NR⁴CO₂R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴C(S)NR⁵R⁶, —NR⁴C(═NH)NR⁵R⁶, —SO₂NR⁴R⁵, —NR⁴SO₂R⁵, —NR⁴SO₂NR⁵R⁶,—B(OR⁴)(OR⁵), —P(O)(OR⁴)(OR⁵), or —P(O)(R⁴)(OR⁵); C is —OR⁷,—S(O)_(b)R⁷, SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹,—NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, —NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR⁸),—P(O)(OR⁷)(OR⁸), —P(O)(R⁷)(OR⁸), or heteroaryl (for example, tetrazole);D is an aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring wherein the ring is optionally fused to anotheraryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl ring; a and b are independently 0, 1 or 2; and R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl; or alternatively, R¹ and R², R² and R³, R⁴ and R⁵, R⁵and R⁶, R⁷ and R⁸, or R⁸ and R⁹, together with the atoms to which theyare bonded, form a cycloheteroalkyl or substituted cycloheteroalkylring.

In another embodiment, the present invention provides an ingestiblecomposition comprising a compound of the present invention and aningestibly acceptable excipient.

In another embodiment, the present invention provides a flavoringconcentrate formulation comprising a compound of the present inventionand a carrier.

In another embodiment, the present invention provides a method ofmodulating the sweet taste of an ingestible composition comprisingcontacting the ingestible composition or precursors thereof with acompound of the present invention to form a modified ingestiblecomposition.

In another embodiment, the present invention provides a method forpreparing a compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

These and other embodiments, advantages, and features of the presentinvention are provided in the sections below. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

DEFINITIONS

“Alkyl,” by itself or as part of another substituent, refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. The term“alkyl” includes “cycloalkyl” as defined herein below. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Theterm “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms (C₁-C₂₀ alkyl). In otherembodiments, an alkyl group comprises from 1 to 10 carbon atoms (C₁-C₁₀alkyl). In still other embodiments, an alkyl group comprises from 1 to 6carbon atoms (C₁-C₆ alkyl). It is noted that when an alkyl group isfurther connected to another atom, it becomes an “alkylene” group. Inother words, the term “alkylene” refers to a divalent alkyl. Forexample, —CH₂CH₃ is an ethyl, while —CH₂CH₂— is an ethylene. That is,“Alkylene,” by itself or as part of another substituent, refers to asaturated or unsaturated, branched, straight-chain or cyclic divalenthydrocarbon radical derived by the removal of two hydrogen atoms from asingle carbon atom or two different carbon atoms of a parent alkane,alkene or alkyne. The term “alkylene” includes “cycloalkylene” asdefined herein below. The term “alkylene” is specifically intended toinclude groups having any degree or level of saturation, i.e., groupshaving exclusively single carbon-carbon bonds, groups having one or moredouble carbon-carbon bonds, groups having one or more triplecarbon-carbon bonds and groups having mixtures of single, double andtriple carbon-carbon bonds. Where a specific level of saturation isintended, the expressions “alkanylene,” “alkenylene,” and “alkynylene”are used. In some embodiments, an alkylene group comprises from 1 to 20carbon atoms (C₁-C₂₀ alkylene). In other embodiments, an alkylene groupcomprises from 1 to 10 carbon atoms (C₁-C₁₀ alkylene). In still otherembodiments, an alkylene group comprises from 1 to 6 carbon atoms (C₁-C₆alkylene).

“Alkanyl,” by itself or as part of another substituent, refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. The term “alkanyl” includes “cycloakanyl” as defined hereinbelow. Typical alkanyl groups include, but are not limited to, methanyl;ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl),cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl(sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl(t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl,” by itself or as part of another substituent, refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The term“alkenyl” includes “cycloalkenyl” as defined herein below. The group maybe in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl,” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Alkoxy,” by itself or as part of another substituent, refers to aradical of the formula —O—R¹⁹⁹, where R¹⁹⁹ is alkyl or substituted alkylas defined herein.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R²⁰⁰, where R²⁰⁰ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkylas defined herein. Representative examples include, but are not limitedto formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl,benzoyl, benzylcarbonyl and the like.

“Aryl,” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem, as defined herein. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms (C₆-C₂₀aryl). In other embodiments, an aryl group comprises from 6 to 15 carbonatoms (C₆-C₁₅ aryl). In still other embodiments, an aryl group comprisesfrom 6 to 15 carbon atoms (C₆-C₁₀ aryl).

“Arylalkyl,” by itself or as part of another substituent, refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group as, as defined herein. Typical arylalkyl groups include,but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl,naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specificalkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyland/or arylalkynyl is used. In some embodiments, an arylalkyl group is(C₆-C₃₀) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₁₀) alkyl and the aryl moiety is (C₆-C₂₀) aryl.In other embodiments, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g.,the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₈)alkyl and the aryl moiety is (C₆-C₁₂) aryl. In still other embodiments,an arylalkyl group is (C₆-C₁₅) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₅) alkyl and the arylmoiety is (C₆-C₁₀) aryl.

“Cycloalkyl,” or “Carbocyclyl,” by itself or as part of anothersubstituent, refers to a saturated or unsaturated cyclic alkyl radical,as defined herein. Similarly, “Cycloalkylene,” or “Carbocyclylene,” byitself or as part of another substituent, refers to a saturated orunsaturated cyclic alkylene radical, as defined herein. Where a specificlevel of saturation is intended, the nomenclature “cycloalkanyl”,“cycloalkenyl”, or “cycloalkynyl” is used. Typical cycloalkyl groupsinclude, but are not limited to, groups derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane, and the like. In someembodiments, the cycloalkyl group comprises from 3 to 10 ring atoms(C₃-C₁₀ cycloalkyl). In other embodiments, the cycloalkyl groupcomprises from 3 to 7 ring atoms (C₃-C₇ cycloalkyl). The cycloalkyl maybe further substituted by one or more heteroatoms including, but notlimited to, N, P, O, S, and Si, which attach to the carbon atoms of thecycloalkyl via monovalent or multivalent bond.

“Heteroalkyl,” “Heteroalkanyl,” “Heteroalkenyl” and “Heteroalkynyl,” bythemselves or as part of other substituents, refer to alkyl, alkanyl,alkenyl and alkynyl groups, respectively, in which one or more of thecarbon atoms (and optionally any associated hydrogen atoms), are each,independently of one another, replaced with the same or differentheteroatoms or heteroatomic groups. Similarly, “Heteroalkylene,”“Heteroalkanylene,” “Heteroalkenylene” and “Heteroalkynylene,” bythemselves or as part of other substituents, refer to alkylene,alkanylene, alkenylene and alkynyenel groups, respectively, in which oneor more of the carbon atoms (and optionally any associated hydrogenatoms), are each, independently of one another, replaced with the sameor different heteroatoms or heteroatomic groups. Typical heteroatoms orheteroatomic groups which can replace the carbon atoms include, but arenot limited to, —O—, —S—, —N—, —Si—, —NH—, —S(O)—, —S(O)₂—, —S(O)NH—,—S(O)₂NH— and the like and combinations thereof. The heteroatoms orheteroatomic groups may be placed at any interior position of the alkyl,alkenyl or alkynyl groups. Typical heteroatomic groups which can beincluded in these groups include, but are not limited to, —O—, —S—,—O—O—, —S—S—, —O—S—, —NR²⁰¹R²⁰²—, ═N—N═, —N═N—, —N═N—NR²⁰³R²⁰⁴, —PR²⁰⁵—,—P(O)₂—, —POR²⁰⁶—, —O—P(O)₂—, —SO—, —SO₂—, —SnR²⁰⁷R²⁰⁸— and the like,where R²⁰¹, R²⁰², R²⁰³, R²⁰⁴, R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ areindependently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl.

“Cycloheteroalkyl,” or “Heterocyclyl,” by itself or as part of anothersubstituent, refers to a saturated or unsaturated cyclic alkyl radicalin which one or more carbon atoms (and optionally any associatedhydrogen atoms) are independently replaced with the same or differentheteroatom. Similarly, “Cycloheteroalkylene,” or “Heterocyclylene,” byitself or as part of another substituent, refers to a saturated orunsaturated cyclic alkylene radical in which one or more carbon atoms(and optionally any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom. The cycloheteroalkyl maybe further substituted by one or more heteroatoms including, but notlimited to, N, P, O, S, and Si, which attach to the carbon atoms of thecycloheteroalkyl via monovalent or multivalent bond. Typical heteroatomsto replace the carbon atom(s) include, but are not limited to, N, P, O,S, Si, etc. Where a specific level of saturation is intended, thenomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.Typical cycloheteroalkyl groups include, but are not limited to, groupsderived from epoxides, azirines, thiiranes, imidazolidine, morpholine,piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, and thelike. In some embodiments, the cycloheteroalkyl group comprises from 3to 10 ring atoms (3-10 membered cycloheteroalkyl) In other embodiments,the cycloalkyl group comprise from 5 to 7 ring atoms (5-7 memberedcycloheteroalkyl). A cycloheteroalkyl group may be substituted at aheteroatom, for example, a nitrogen atom, with a (C₁-C₆) alkyl group. Asspecific examples, N-methyl-imidazolidinyl, N-methyl-morpholinyl,N-methyl-piperazinyl, N-methyl-piperidinyl, N-methyl-pyrazolidinyl andN-methyl-pyrrolidinyl are included within the definition of“cycloheteroalkyl.” A cycloheteroalkyl group may be attached to theremainder of the molecule via a ring carbon atom or a ring heteroatom.

“Compounds” refers to compounds encompassed by structural formulaedisclosed herein, such as (I), (II), (IIa), (IIb), (III), (IIIa),(IIIb), (IIIc), and (IIId), and includes any specific compounds withinthese formulae whose structure is disclosed herein. Compounds may beidentified either by their chemical structure and/or chemical name. Whenthe chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound. Thecompounds described herein may contain one or more chiral centers and/ordouble bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds may alsoexist in several tautomeric forms including the enol form, the keto formand mixtures thereof. Accordingly, the chemical structures depictedherein encompass all possible tautomeric forms of the illustratedcompounds. The term “tautomer” as used herein refers to isomers thatchange into one another with great ease so that they can exist togetherin equilibrium. In general, compounds may be hydrated, solvated orN-oxides. Certain compounds may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated herein and are intended to be within the scope of thepresent invention. Further, it should be understood, when partialstructures of the compounds are illustrated, that brackets indicate thepoint of attachment of the partial structure to the rest of themolecule.

“Halo,” by itself or as part of another substituent refers to a radical—F, —Cl, —Br or —I.

“Heteroaryl,” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring systems, asdefined herein. Typical heteroaryl groups include, but are not limitedto, groups derived from acridine, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In some embodiments, the heteroaryl group comprises from 5 to 20ring atoms (5-20 membered heteroaryl). In other embodiments, theheteroaryl group comprises from 5 to 10 ring atoms (5-10 memberedheteroaryl). Exemplary heteroaryl groups include those derived fromfuran, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole,indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole andpyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In some embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In other embodiments,the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety is (C₁-C₃) alkyl and the heteroarylmoiety is a 5-10 membered heteroaryl.

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Salt” refers to a salt of a compound, which possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Solvate” means a compound formed by solvation (the combination ofsolvent molecules with molecules or ions of the solute), or an aggregatethat consists of a solute ion or molecule, i.e., a compound of thepresent invention, with one or more solvent molecules. When water is thesolvent, the corresponding solvate is “hydrate”.

“N-oxide”, also known as amine oxide or amine-N-oxide, means a compoundthat derives from a compound of the present invention via oxidation ofan amine group of the compound of the present invention. An N-oxidetypically contains the functional group R₃N⁺—O⁻ (sometimes written asR₃N═O or R₃N→O).

“Substituted,” when used to modify a specified group or radical, meansthat one or more hydrogen atoms of the specified group or radical areeach, independently of one another, replaced with the same or differentsubstituent(s). Substituent groups useful for substituting saturatedcarbon atoms in the specified group or radical include, but are notlimited to —R^(a), halo, —O⁻, ═O, —OR^(b), —SR^(b), —S⁻, ═S,—NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)s may be taken together with the nitrogenatom to which they are bonded form a 4-, 5-, 6- or 7-memberedcycloheteroalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S. As specific examples, —NR^(c)R^(c) is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl and N-morpholinyl. As another specificexample, a substituted alkyl is meant to include -alkylene-O-alkyl,-alkylene-heteroaryl, -alkylene-cycloheteroalkyl, -alkylene-C(O)OR^(b),-alkylene-C(O)NR^(b)R^(b), and —CH₂—CH₂—C(O)—CH₃. The one or moresubstituent groups, taken together with the atoms to which they arebonded, may form a cyclic ring including cycloalkyl andcycloheteroalkyl.

Similarly, substituent groups useful for substituting unsaturated carbonatoms in the specified group or radical include, but are not limited to,—R^(a), halo, —O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl,—CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)₂R^(b), —S(O)₂O⁻,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O⁻, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined.

Substituent groups useful for substituting nitrogen atoms in heteroalkyland cycloheteroalkyl groups include, but are not limited to, —R^(a),—O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c), trihalomethyl, —CF₃, —CN, —NO,—NO₂, —S(O)₂R^(b), —S(O)₂O⁻, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻,—OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)),—C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b), —C(S)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b),—OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b),—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a),R^(b) and R^(c) are as previously defined.

Substituent groups from the above lists useful for substituting otherspecified groups or atoms will be apparent to those of skill in the art.

The substituents used to substitute a specified group can be furthersubstituted, typically with one or more of the same or different groupsselected from the various groups specified above.

“Vehicle” refers to a diluent, adjuvant, excipient or carrier with whicha compound is administered.

As used herein, an “ingestible composition” includes any substance that,either alone or together with another substance, can be taken by mouthwhether intended for consumption or not. The ingestible compositionincludes both “food or beverage products” and “non-edible products”. By“Food or beverage products”, it is meant any edible product intended forconsumption by humans or animals, including solids, semi-solids, orliquids (e.g., beverages). The term “non-edible products” or“noncomestible composition” includes any product or composition that canbe taken by humans or animals for purposes other than consumption or asfood or beverage. For example, the non-edible product or noncomestiblecomposition includes supplements, nutraceuticals, functional foodproducts (e.g., any fresh or processed food claimed to have ahealth-promoting and/or disease-preventing properties beyond the basicnutritional function of supplying nutrients), pharmaceutical and overthe counter medications, oral care products such as dentifrices andmouthwashes, cosmetic products such as sweetened lip balms and otherpersonal care products that may or may not contain any sweetener.

A “ingestibly acceptable carrier or excipient” is a medium and/orcomposition that is used to prepare a desired dispersed dosage form ofthe inventive compound, in order to administer the inventive compound ina dispersed/diluted form, so that the biological effectiveness of theinventive compound is maximized. The medium and/or composition may be inany form depending on the intended use of a product, e.g., solid,semi-solid, liquid, paste, gel, lotion, cream, foamy material,suspension, solution, or any combinations thereof (such as a liquidcontaining solid contents). Ingestibly acceptable carriers includes manycommon food ingredients, such as water at neutral, acidic, or basic pH,fruit or vegetable juices, vinegar, marinades, beer, wine, naturalwater/fat emulsions such as milk or condensed milk, edible oils andshortenings, fatty acids and their alkyl esters, low molecular weightoligomers of propylene glycol, glyceryl esters of fatty acids, anddispersions or emulsions of such hydrophobic substances in aqueousmedia, salts such as sodium chloride, wheat flours, solvents such asethanol, solid edible diluents such as vegetable powders or flours, orother liquid vehicles; dispersion or suspension aids; surface activeagents; isotonic agents; thickening or emulsifying agents,preservatives; solid binders; lubricants and the like.

An “enhancer” herein refers to a compound, or an ingestibly acceptablesalt or solvate thereof, that modulates (increases) the activation of aparticular receptor, preferably the chemosensory, e.g., T1R2/T1R3receptor. Herein such enhancers will enhance the activation of achemosensory receptor by its ligand. Typically the “enhancer” will bespecific to a particular ligand, i.e., it will not enhance theactivation of a chemosensory receptor by chemosensory ligands other thanthe particular chemosensory ligand or ligands closely related thereto.Most enhancers, at its ligand enhancing concentration, do not result insubstantial activation of the particular receptor by themselves. Usuallythe ligand enhancing concentrations of an enhancer are concentrationlevels of the enhancer that increases or enhances the activation of aparticular receptor by a ligand without substantially activating theparticular receptor by the enhancer itself. In some embodiments, certainenhancers, when used at a concentration higher than the ligand enhancingconcentration, can also activate a particular receptor by themselves inaddition to modulating (e.g., increase or enhancement) the activation ofthe receptor. For example, certain enhancers, when used at aconcentration higher than the ligand enhancing concentration, can besweeteners (i.e., sweet flavoring agent/entity) as well.

A “flavor” herein refers to the perception of taste in a subject, whichinclude sweet, sour, salty, bitter and umami. The subject may be a humanor an animal.

A “flavoring agent” herein refers to a compound or the ingestiblyacceptable salt or solvate thereof that induces a flavor or taste in ananimal or a human. The flavoring agent can be natural, semi-synthetic,or synthetic.

A “flavor modifier” or “flavor modifying agent” herein refers to acompound or the ingestibly acceptable salt or solvate thereof thatmodulates, including enhancing or potentiating, and/or inducing, thetastes of a flavoring agent in an animal or a human.

A “flavor enhancer” herein refers to a compound or ingestibly acceptablesalt thereof that enhances and/or multiplies the tastes of a flavoringagent, or an ingestible composition comprising the flavoring agent.

A “sweet flavor” refers to the sweet taste typically induced by sugar,such as sucrose, in an animal or a human.

A “sweet flavoring agent”, “sweet flavor entity”, “sweetener”, “sweetcompound”, or “sweet receptor activating compound” herein refers to acompound or ingestibly acceptable salt thereof that elicits a detectablesweet flavor in a subject, e.g., sucrose or a compound that activates aT1R2/T1R3 receptor in vitro. The subject may be a human or an animal.

A “sweet flavor modifier” or “sweet flavor modifying agent” hereinrefers to a compound or ingestibly acceptable salt or solvate thereofthat modulates, including enhancing or potentiating, inducing, orblocking, the sweet taste of a sweet flavoring agents in an animal or ahuman. The sweet flavor modifier includes both sweet flavor enhancer andsweet flavoring agent.

A “sweet flavor enhancer” or “sweet flavor enhancing agent” hereinrefers to an enhancer of a sweet flavor wherein the term enhancer is thesame as defined above.

A “sweet receptor activating compound” herein refers to a compound thatactivates a sweet receptor, such as a T1R2/T1R3 receptor. One example ofa sweet receptor activating compound is a sweetener, such as sucrose.

A “sweet receptor modulating compound” herein refers to a compound thatmodulates (activates, block, or enhances/reduces activation of) a sweetreceptor such as a T1R2/T1R3 receptor.

A “sweet receptor enhancing compound” herein refers to a compound thatenhances or potentiates the effect of a sweet receptor activatingcompound, e.g., sucrose.

Although most sweet receptor enhancing compounds or sweet flavorenhancers, at its ligand enhancing concentration of use, do not resultin substantial activation of the particular receptor by themselves, someof the sweet receptor enhancing compounds or sweet flavor enhancers,when used at a concentration higher than its ligand enhancingconcentration, can also activate a particular receptor by themselves inaddition to modulating (increase) the activation of the receptor. Forexample, some of the sweet receptor enhancing compounds or sweet flavorenhancers, when used at a concentration higher than their ligandenhancing concentrations, can also activate a sweet receptor, such as aT1R2/T1R3 receptor, acting as the receptor agonists.

A “sweet flavor modulating amount” herein refers to an amount of acompound of Formula (I) that is sufficient to alter (either increase ordecrease) sweet taste in an ingestible composition, or a precursorthereof, sufficiently to be perceived by a human subject. In manyembodiments of the invention, at least about 0.001 ppm of the presentcompound would need to be present in order for most human subjects toperceive a modulation of the sweet flavor of an ingestible compositioncomprising the present compound. A broad range of concentration thatwould typically be employed in order to economically provide a desirabledegree of sweet flavor modulation can be from about 0.001 ppm to 100ppm, or a narrow range from about 0.1 ppm to about 10 ppm. Alternativeranges of sweet flavor modulating amounts can be from about 0.01 ppm toabout 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm toabout 5 ppm, or from about 0.1 ppm to about 3 ppm.

A “sweet flavor enhancing amount” herein refers to an amount of acompound that is sufficient to enhance the taste of flavoring agents,e.g., sucrose, in a ingestible composition, as perceived by an animal ora human. A broad range of a sweet flavor enhancing amount can be fromabout 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm toabout 10 ppm. Alternative ranges of sweet flavor enhancing amounts canbe from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3ppm. In some embodiments, sweet flavor enhancing amount is the amountcorresponding to ligand enhancing concentration(s) of a sweet flavorenhancer of the present invention.

A “sweet receptor modulating amount” herein refers to an amount of acompound that is sufficient to modulate (activate, enhance or block) asweet taste receptor protein. In many embodiments of the invention, asweet receptor modulating amount is at least about 1 pM, or at leastabout 1 nM, or at least about 10 nM, or at least about 100 nM (i.e.about 0.1 μM). A “T1R2/T1R3 receptor modulating or activating amount” isan amount of compound that is sufficient to modulate or activate aT1R2/T1R3 receptor. A “sweet receptor” is a taste receptor that can bemodulated by a sweet compound. Preferably a sweet receptor is a Gprotein coupled receptor, and more preferably the sweet receptor is aT1R2/T1R3 receptor.

Compounds

In one embodiment, the present invention provides a compound havingstructural Formula (I) or (I′):

or a tautomer, salt, and/or solvate, wherein: A is —OR¹, —NR¹C(O)R²,—NHOR¹, —NR¹R², —NR¹CO₂R², —NR¹C(O)NR²R³, —NR¹C(S)NR²R³ or—NR¹C(═NH)NR²R³; B is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, acyl, substitutedacyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —CN, —OR⁴,—S(O)_(a)R⁴, —NR⁴R⁵, —C(O)NR⁴R⁵, —CO₂R⁴, —NR⁴CO₂R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴C(S)NR⁵R⁶, —NR⁴C(═NH)NR⁵R⁶, —SO₂NR⁴R⁵, —NR⁴SO₂R⁵, —NR⁴SO₂NR⁵R⁶,—B(OR⁴)(OR⁵), —P(O)(OR⁴)(OR⁵), or —P(O)(R⁴)(OR⁵); is —OR⁷, —S(O)^(b)R⁷,SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷C(═N)NR⁸R⁹,—SO₂NR⁷R⁸, —NR⁷SO₂R⁸, —NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR⁸),—P(O)(R⁷)(OR⁸), or heteroaryl (for example, tetrazole); D is an aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring wherein the ring is optionally fused to another aryl, substitutedaryl, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring; aand b are independently 0, 1 or 2; and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,and R⁹ are independently hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, acyl, substitutedacyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; oralternatively, R¹ and R², R² and R³, R⁴ and R⁵, R⁵ and R⁶, R⁷ and R⁸, orR⁸ and R⁹, together with the atoms to which they are bonded, form acycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment of the present invention, the Formula (I) is subjectto the following provisos: (a) when D is substituted phenyl; B ishydrogen; C is —CO₂R⁷; R⁷ is hydrogen or alkyl; A is —NR¹R²; and one ofR¹ and R² is hydrogen; then the other of R¹ and R² is not substitutedarylalkyl; and (b) when D is phenyl or substituted phenyl; C is —CO₂R⁷;R⁷ is alkyl; A is —NR¹R²; and R¹ and R² are both hydrogen; then B is not—CO₂R⁴; wherein R⁴ is alkyl.

In one embodiment of the present invention, the Formula (I) does notinclude the following compounds:8-Bromo-4-(4-methoxybenzyl)amino-5-methoxyquinoline-3-carboxylic acidethyl ester; 4-(4-Methoxybenzyl)amino-5-methoxyquinoline-3-carboxylicacid ethyl ester;4-(4-Methoxybenzyl)amino-5-methoxyquinoline-3-carboxylic acid;4-(4-Methoxybenzyl)amino-8-methoxyquinoline-3-carboxylic acid ethylester; 4-(4-Methoxybenzyl)amino-8-methoxyquinoline-3-carboxylic acid;4-Amino-3-ethoxycarbonyl-2-ethoxycarbonylmethylquinoline; and4-Amino-3-ethoxycarbonyl-2-ethoxycarbonylmethyl-5-methoxyquinoline.

In one embodiment of Formula (I), R¹ and R² are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, acyl,substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;or alternatively, R¹ and R², R² and R³, R⁴ and R⁵, R⁵ and R⁶, R⁷ and R⁸,or R⁸ and R⁹, together with the atoms to which they are bonded, form acycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment of Formula (I), when B is substituted alkyl, then thesubstituent on the alkyl is not —C(O)OR^(b); where R^(b) is alkyl.

In one embodiment of Formula (I), when B is substituted alkyl, then thesubstituent on the alkyl is selected from the group consisting of—R^(a), halo, —O⁻, ═O, —OR^(b), —SR^(b), —S⁻, ═S, —NR^(c)R^(c), ═NR^(b),═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃,—S(O)₂R^(b), —S(O)₂N^(b), —S(O)₂O⁻, —S(O)₂OR^(b), —OS(O)₂R^(b),—OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻,—C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b),—OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b),—NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)s may be taken together with the nitrogenatom to which they are bonded form a 4-, 5-, 6- or 7-memberedcycloheteroalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S.

In one embodiment of the present invention, the compounds of Formula (I)or (I′) have a structural Formula (II) or (II′),

or a tautomer, salt, and/or solvate, wherein: Y forms a single bond witheither W or Z and a double bond with the other of W or Z; W is —C(R¹⁰)—,—S—, —N—, —N(R¹¹)—, or —O—; Y is —C(R¹²)— or —N—; Z is —C(R¹³)—, —S—,—N—, —N(R¹⁴)—, or —O—; R¹⁰ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, acyl, substitutedacyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, halo, —CN,—OR¹⁵, —S(O)_(c)R¹⁵, —NR¹⁵R¹⁶, —C(O)NR¹⁵R¹⁶, —CO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—NR¹⁵SO₂R¹⁶, —P(O)(OR¹⁵)(OR¹⁶) or —P(O)(R¹⁵)(OR¹⁶); R¹² is hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, halo, —CN, —OR¹⁷, —S(O)_(d)R¹⁷, —OC(O)R¹⁷, —NR¹⁷R¹⁸,—C(O)NR¹⁷R¹⁸, —CO₂R¹⁷, —SO₂NR¹⁷R¹⁸, —NR¹⁷SO₂R¹⁸, —P(O)(OR¹⁷)(OR¹⁸) or—P(O)(R¹⁷)(OR¹⁸); R¹³ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, acyl, substitutedacyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, halo, —CN,—OR¹⁹, —S(O)_(e)R¹⁹, —OC(O)R¹⁹, —NR¹⁹R²⁰, —C(O)NR¹⁹R²⁰, —C(O)R¹⁹,—CO₂R¹⁹, —SO₂NR¹⁹R²⁰, —NR¹⁹SO₂R²⁰, —P(O)(OR¹⁹)(OR²⁰) or—P(O)(R¹⁹)(OR²⁰); or alternatively R¹⁰ and R¹², or R¹² and R¹³, togetherwith the atoms to which they are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring; c, d and e are independently 0, 1, or 2; R¹¹ and R¹⁴ areindependently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl; or alternatively R¹⁵ and R¹⁶, R¹⁷ and R¹⁸, or R¹⁹ andR²⁰, together with the atoms to which they are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring; and with thefollowing provisos: (a) when W is —O— or —S— or —NR¹¹—, then Z is—C(R¹³)— or —N—; (b) when Z is —O— or —S— or —NR¹⁴—, then W is —C(R¹⁰)—or —N—; and (c) when W is —C(R¹⁰)— or —N—, then Z cannot be —C(R¹³)— or—N—.

In one embodiment of the present invention, the compounds of Formula(II) or (II′) have a structural Formula (IIa) or (IIa′),

or a tautomer, salt, and/or solvate, wherein, W is —C(R¹⁰)—, or —N—; Yis —C(R¹²)— or —N—; and Z is —S—, —N(R¹⁴)—, or —O—.

In one embodiment of the present invention, the compounds of Formula(II) or (II′) have a structural Formula (IIb) or (IIb′),

or a tautomer, salt, and/or solvate, wherein, W is —S—, —N(R¹¹)—, or—O—; Y is —C(R¹²)— or —N—; and Z is —C(R¹³)—, or —N—.

In one embodiment of the present invention, the compounds of Formula (I)or (I′) have a structural Formula (III) or (III′),

or a tautomer, salt, and/or solvate thereof, wherein: H is —C(R²¹)— or—N—; I is —C(R²²) or —N—; J is —C(R²³)— or —N—; K is —C(R²⁴)— or —N—;R²¹ is hydrogen, alkyl, substituted alkyl, halo, —CN, —OR²⁵; R²² ishydrogen, alkyl, substituted alkyl, halo, —CN, —OR²⁷; R²³ is hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, —CN, —OR²⁹, —S(O)_(f)R²⁹, —OC(O)R²⁹,—NR²⁹R³⁰, —C(O)NR²⁹R³⁰, —CO₂R²⁹, —SO₂NR²⁹R³⁰, —NR²⁹SO₂R³⁰,—B(OR²⁹)(OR³⁰), —P(O)(OR²⁹)(OR³⁰) or —P(O)(R²⁹)(OR³⁰); R²⁴ is hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, —CN, —OR³¹, —S(O)_(g)R³¹, —OC(O)R³¹,—NR³¹R³², —C(O)NR³¹R³², —C(O)R³¹, —CO₂R³¹, —SO₂NR³¹R³², —NR³¹SO₂R³²,—B(OR³¹)(OR³²), —P(O)(OR³¹)(OR³²) or —P(O)(R³¹)(OR³²); or alternativelyR²³ and R²⁴, taken together with the atom to which they are attached,form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, orsubstituted cycloheteroalkyl ring; f and g are independently 0, 1 or 2;and R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, and R³² are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, orsubstituted heteroarylalkyl; or alternatively R²⁵ and R²⁶, R²⁷ and R²⁸,R²⁹ and R³⁰, or R³¹ and R³², together with the atoms to which they areattached, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;with the proviso that at most, two of H, I, J and K are —N—.

In one embodiment of Formula (III), one or two of H, I, J and K are —N—.

In one embodiment of Formula (III), H is —N—, I is —C(R²²)—, J is—C(R²³)—, and K is —C(R²⁴)—.

In one embodiment of Formula (III), H is —C(R²¹)—, I is —N—, J is—C(R²³)—, and K is —C(R²⁴)—.

In one embodiment of Formula (III), H is —C(R²¹)—, I is —C(R²²)—, J is—N—, and K is —C(R²⁴)—.

In one embodiment of Formula (III), H is —C(R²¹)—, I is —C(R²²), J is—C(R²³)—, and K is —N—.

In one embodiment of Formula (III), H and I are —N—.

In one embodiment of Formula (III), H and J are —N—.

In one embodiment of Formula (III), H and K are —N—.

In one embodiment of Formula (III), I and J are —N—.

In one embodiment of Formula (III), I and K are —N—.

In one embodiment of Formula (III), J and K are —N—.

In one embodiment of the present invention, the compounds of Formula(III) or (III′) have a structural Formula (IIIa) or (IIIa′),

or a tautomer, salt, and/or solvate thereof.

In one embodiment of Formula (IIIa), two or three of R²¹, R²², R²³, andR²⁴ are hydrogen.

In one embodiment of Formula (IIIa), R²¹ is hydrogen; R²² is hydrogen,alkyl, substituted alkyl, halo, —CN, or —OR²⁷; R²³ is hydrogen, alkyl,substituted alkyl, —CN, —OR²⁹, —S(O)_(f)R²⁹, —OC(O)R²⁹, —NR²⁹R³⁰,—C(O)NR²⁹R³⁰, —C(O)R²⁹, —CO₂R²⁹, —SO₂NR²⁹R³⁰, or —NR²⁹SO₂R³⁰; R²⁴ ishydrogen, alkyl, substituted alkyl, —CN, —OR³¹, —S(O)_(g)R³¹, —OC(O)R³¹,—NR³¹R³², —C(O)NR³¹R³², —C(O)R³¹, —CO₂R³¹, —SO₂NR³¹R³², or —NR³¹SO₂R³²;or alternatively R²³ and R²⁴, taken together with the atoms to whichthey are attached, form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, or substituted cycloheteroalkyl ring; and R²⁷, R²⁹,R³⁰, R³¹, and R³² are independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl,substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;or alternatively R²⁵ and R²⁶, R²⁷ and R²⁸, R²⁹ and R³⁰, or R³¹ and R³²,together with the atoms to which they are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment of Formula (IIIa), R²¹ and R²² are all hydrogen.

In one embodiment of Formula (IIIa), R²³ and R²⁴, taken together withthe atom to which they are attached, form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring.

In one embodiment of Formula (IIIa), R²³ and R²⁴, taken together withthe atom to which they are attached, form a substituted cycloheteroalkylring containing one or more substituents selected from the groupconsisting of —R^(a), halo, —O⁻, ═O, —OR^(b), —SR^(b), —S⁻, ═S,—NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(O)OR^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)O⁻, —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻,—NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) isselected from the group consisting of alkyl, cycloalkyl, heteroalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; eachR^(b) is independently hydrogen or R^(a); and each R^(c) isindependently R^(b) or alternatively, the two R^(c)s may be takentogether with the nitrogen atom to which they are bonded form a 4-, 5-,6- or 7-membered cycloheteroalkyl which may optionally include from 1 to4 of the same or different additional heteroatoms selected from thegroup consisting of O, N and S; or alternatively, two of thesubstituents on the cycloheteroalkyl ring, together with the atoms towhich they are bonded, form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, or substituted cycloheteroalkyl ring.

In one embodiment of Formula (IIIa), R²¹, R²², R²³, and R²⁴ are allhydrogen.

In one embodiment of Formula (IIIa), A is —OR¹, —NR¹C(O)R², —NHOR¹,—NR¹R₂, —NOR¹, —NR¹CO₂R², —NR¹C(O)NR²R³, —NR¹CSNR²R³, or—NR¹C(═NH)NR²R³.

In one embodiment of Formula (IIIa), C is —S(O)_(b)R⁷, SO₃R⁷,—C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷C(S)NR⁸R⁹,—NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, —NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR⁸),—P(O)(OR⁷)(OR⁸), or —P(O)(R⁷)(OR⁸).

In one embodiment of Formula (IIIa), B is hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl,substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

In one embodiment of Formula (IIIa), three of R²¹, R²², R²³, and R²⁴ arehydrogen; A is —OR¹, —NR¹C(O)R², —NHOR¹, —NR¹R², —NR¹CO₂R²,—NR¹C(O)NR²R³, —NR¹C(S)NR²R³, or —NR¹C(═NH)NR²R³; C is —S(O)_(b)R⁷,SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷C(S)NR⁸R⁹,—NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, —NR⁷SO₂NR⁸R⁹, —B(OR⁷)(OR⁸),—P(O)(OR⁷)(OR⁸), or —P(O)(R⁷)(OR⁸) or tetrazole; B is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.

In one embodiment of the present invention, the compounds of Formula(IIIa) or (IIIa′) have a structural Formula (IIIb) or (IIIb′),

or a tautomer, salt, and/or solvate thereof; wherein L¹ is alkylene orsubstituted alkylene; L² is —NR³⁴—, —O—, —S—, —NR³⁴—C(O)—, —C(O)—NR³⁴—,—O—C(O)—, —C(O)—O—, —NR³⁴—C(O)—O—, —O—C(O)—NR³⁴—, —NR³⁴—C(O)—NR³⁵—,—O—C(O)—O—, -hetercyclylene-C(O)—, or -(substitutedhetercyclylene)-C(O)—; R³³ is alkyl, substituted alkyl, carbocyclyl,substituted carbocyclyl; aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heterocyclyl, substituted heterocyclyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, or substituted heteroarylalkyl; and R³⁴ and R³⁵ areindependently hydrogen, alkyl, substituted alkyl, carbocyclyl,substituted carbocyclyl; aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heterocyclyl, substituted heterocyclyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, or substituted heteroarylalkyl.

In one embodiment of the present invention, the compounds of Formula(IIIb) or (IIIb′) have a structural Formula (IIIc), (IIIc′), (IIId), or(IIId′),

or a tautomer, salt, and/or solvate thereof; wherein R³³ is alkyl,substituted alkyl, carbocyclyl, substituted carbocyclyl; aryl,substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl,substituted heterocyclyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.

In one embodiment of Formula (IIIc) or (IIId), R³³ is alkyl, substitutedalkyl, carbocyclyl, substituted carbocyclyl; heterocyclyl, substitutedheterocyclyl, heteroalkyl, or substituted heteroalkyl.

In one embodiment of Formula (IIIb), (IIIc), or (IIId), A is —OR¹,—NR¹C(O)R², —NHOR¹, —NR¹R², —NR¹CO₂R², —NR¹C(O)NR²R³, —NR¹CSNR²R³, or—NR¹C(═NH)NR²R³.

In one embodiment of Formula (IIIb), (IIIc), or (IIId), C is—S(O)_(b)R⁷, SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —NR⁷CO₂R⁸, —NR⁷C(O)NR⁸R⁹,—NR⁷C(S)NR⁸R⁹, —NR⁷C(═NH)NR⁸R⁹, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, —NR⁷SO₂NR⁸R⁹,—B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR⁸), or —P(O)(R⁷)(OR⁸).

In one embodiment of Formula (IIIb), (IIIc), or (IIId), B is hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.

In one embodiment of Formula (IIIb), A is —OR¹, —NHOR¹, or —NR¹R²; B ishydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; C is—SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —SO₂NR⁷R⁸, —B(OR⁷)(OR⁸), —P(O)(OR⁷)(OR⁸), or—P(O)(R⁷)(OR⁸); L¹ is alkylene or substituted alkylene; L² is —NR³⁴—,—O—, —NR³⁴—C(O)—, —C(O)—NR³⁴—, —O—C(O)—, —C(O)—O—,-hetercyclylene-C(O)—, or -(substituted hetercyclylene)-C(O)—; R³³ isalkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl; aryl,substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl,substituted heterocyclyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl; and R³⁴ and R³⁵ are independently hydrogen, alkyl, orsubstituted alkyl.

In one embodiment of Formula (IIIc) or (IIId), A is —OR¹, —NHOR¹, or—NR¹R²; B is hydrogen, alkyl, substituted alkyl, aryl, or substitutedaryl; C is —SO₃R⁷, —C(O)NR⁷R⁸, —CO₂R⁷, —SO₂NR⁷R⁸, —B(OR⁷)(OR⁸),—P(O)(OR⁷)(OR⁸), or —P(O)(R⁷)(OR⁸); R³³ is alkyl, substituted alkyl,carbocyclyl, substituted carbocyclyl; heterocyclyl, substitutedheterocyclyl, heteroalkyl, or substituted heteroalkyl.

In some specific embodiments of the present invention, the compound isselected from the group consisting of

In another embodiment, the present invention provides a method forpreparing a compound of Formula (IV):

wherein B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl; R¹, R², and R⁷ areindependently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; or alternatively, R¹ and R², together withthe atoms to which they are bonded, form a cycloheteroalkyl orsubstituted cycloheteroalkyl ring; R²¹ is hydrogen, alkyl, substitutedalkyl, halo, —CN, —OR²⁵; R²² is hydrogen, alkyl, substituted alkyl,halo, —CN, —OR²⁷; R²³ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, acyl, substitutedacyl, halo, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,—OR²⁹, —S(O)_(f)R²⁹, —OC(O)R²⁹, —NR²⁹R³⁰, —C(O)NR²⁹R³⁰, —CO₂R²⁹,—SO₂NR²⁹R³⁰, —NR²⁹SO₂R³⁰, —B(OR²⁹)(OR³⁰), —P(O)(OR²⁹)(OR³⁰) or—P(O)(R²⁹)(OR³⁰); R²⁴ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, acyl, substitutedacyl, halo, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,—OR³¹, —S(O)_(g)R³¹, —OC(O)R³¹, —NR³¹R³², —C(O)NR³¹R³², —C(O)R³¹,—CO₂R³¹, —SO₂NR³¹R³², —NR³¹SO₂R³², —B(OR³¹)(OR³²), —P(O)(OR³¹)(OR³²) or—P(O)(R³¹)(OR³²); or alternatively R²³ and R²⁴, taken together with theatom to which they are attached, form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring; fand g are independently 0, 1 or 2; and R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰,R³¹, and R³² are independently hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, acyl, substitutedacyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; oralternatively R²⁵ and R²⁶, R²⁷ and R²⁸, R²⁹ and R³⁰, or R³¹ and R³²,together with the atoms to which they are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring.

The method comprises reacting a compound of Formula (IVa):

with a compound of Formula (IVb):

in the presence of a Lewis acid in an anhydrous and non-polar solvent;wherein R^(7b) is alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl; and R²¹, R²², R²³, and R²⁴, are the same as defined inFormula (IV).

When R⁷ in Formula (IV) is hydrogen, then the compound may be obtainedby hydrolyzing the corresponding compound where R⁷ is alkyl orsubstituted alkyl, which in turn can be prepared from the reaction ofthe compounds of Formulae (IVa) and (IVb). Such a hydrolyzationcondition may be basic, acidic, or any condition known to one skilled inthe art.

By “Lewis acid”, it is meant a compound that is an electron-pairacceptor and therefore able to react with a Lewis base to form a Lewisadduct, by sharing the electron pair furnished by the Lewis base. Oneillustrative example is that the reaction of trimethylboron (Lewis acid)and ammonia (Lewis base) to give the adduct Me₃BNH₃. The Lewis acidsuitable for the reaction of compounds of Formulae (IVa) and (IVb) maybe any Lewis acid known to one skilled in the art. In one specificembodiment, the Lewis acid is a metal halide, for example, stannicchloride, boron trihalides, or aluminium chloride.

Solvents for carrying out chemical reactions can be broadly classifiedinto two categories: polar and nonpolar. Generally, the dielectricconstant of the solvent provides a rough measure of a solvent'spolarity. Solvents with a dielectric constant of less than 15 aregenerally considered to be nonpolar. Examples of nonpolar solventsinclude, but are not limited to, pentane, cyclopentane, hexane,cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether,and a combination thereof.

In one embodiment of the method, the reaction of the compound of Formula(IVa) and the compound of Formula (IVb) is conducted at least in part ata temperature of about 60° C. or higher. For example, the reaction maybe conducted at the room temperature in part and at a temperature ofabout 60° C. or higher in part. In one embodiment, the temperature ofabout 60° C. or higher is a temperature of about 70° C. or higher; inanother embodiment, the temperature of about 60° C. or higher is atemperature of about 80° C. or higher; in another embodiment, thetemperature of about 60° C. or higher is a temperature of about 90° C.or higher; in another embodiment, the temperature of about 60° C. orhigher is a temperature of about 100° C. or higher; in anotherembodiment, the temperature of about 60° C. or higher is a temperaturebelow about 130° C.

In one embodiment of Formula (IV), R¹, R², and R⁷ are hydrogen.

In one embodiment of Formula (IV), B is alkyl or substituted alkyl.

In one embodiment of Formula (IV), R²⁴ is —OR³¹, and R³¹ is alkyl,substituted alkyl, carbocyclyl, substituted carbocyclyl; aryl,substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl,substituted heterocyclyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, or substitutedheteroarylalkyl.

In one embodiment of the invention, the compound of Formula (IV) isrepresented by Formula (IVc):

Wherein B is alkyl or substituted alkyl; and R³¹ is alkyl, substitutedalkyl, carbocyclyl, and substituted carbocyclyl.

Compositions

The present compounds can be used for one or more methods of the presentinvention, e.g., modulating or enhancing sweet flavor. In general, thecompounds of the present invention, individually or in combination, canbe provided in a composition, such as, e.g., an ingestible composition.

The compounds of Formula (I) and its various subgenuses, and their saltsand/or solvates, should preferably be comestibly acceptable, e.g.,deemed suitable for consumption in food or drink from the perspective ofgiving unmodified comestible compositions an improved and/or pleasingsweet taste, and would not be significantly toxic or causes unpleasantor undesirable pharmacological or toxicological effects on an animal orhuman at the typical concentrations they are employed as flavoringagents for the comestible compositions.

The typical method of demonstrating that a flavorant compound iscomestibly acceptable is to have the compound tested and/or evaluated byan Expert Panel of the Flavor and Extract Manufacturers Association anddeclared as to be “Generally Recognized As Safe” (“GRAS”). The FEMA/GRASevaluation process for flavorant compounds is complex but well known tothose of ordinary skill in the food product preparation arts, as isdiscussed by Smith, et al. in an article entitled “GRAS FlavoringSubstances 21,” Food Technology, 57(5), pgs 46-59, May 2003, the entirecontents of which are hereby incorporated herein by reference.

In one embodiment, the compounds of the present invention can be used atits ligand enhancing concentrations, e.g., very low concentrations onthe order of a few parts per million, in combination with one or moreknown sweeteners, natural or artificial, so as to reduce theconcentration of the known sweetener required to prepare an ingestiblecomposition having the desired degree of sweetness.

Commonly used known or artificial sweeteners for use in suchcombinations of sweeteners include but are not limited to the commonsaccharide sweeteners, e.g., sucrose, fructose, glucose, and sweetenercompositions comprising natural sugars, such as corn syrup (includinghigh fructose corm syrup) or other syrups or sweetener concentratesderived from natural fruit and vegetable sources, semi-synthetic “sugaralcohol” sweeteners such as erythritol, isomalt, lactitol, mannitol,sorbitol, xylitol, maltodextrin, and the like, and artificial sweetenerssuch as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, andalitame. Sweeteners also include cyclamic acid, mogroside, tagatose,maltose, galactose, mannose, sucrose, fructose, lactose, neotame andother aspartame derivatives, glucose, D-tryptophan, glycine, maltitol,lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starchhydrolyzate (HSH), stevioside, rebaudioside A and other sweetStevia-based glycosides, carrelame and other guanidine-based sweeteners,etc. The term “sweeteners” also includes combinations of sweeteners asdisclosed herein.

In one embodiment, the present compound is added to a noncomestiblecomposition or non-edible product, such as supplements, nutraceuticals,functional food products (e.g., any fresh or processed food claimed tohave a health-promoting and/or disease-preventing properties beyond thebasic nutritional function of supplying nutrients), pharmaceutical andover the counter medications, oral care products such as dentifrices andmouthwashes, cosmetic products such as sweetened lip balms and otherpersonal care products that use sucrose, sucralose and/or othersweeteners.

In general, over the counter (OTC) product and oral hygiene productgenerally refer to product for household and/or personal use which maybe sold without a prescription and/or without a visit to a medicalprofessional. Examples of the OTC products include, but are not limitedto Vitamins and dietary supplements; Topical analgesics and/oranesthetic; Cough, cold and allergy remedies; Antihistamines and/orallergy remedies; and combinations thereof. Vitamins and dietarysupplements include, but are not limited to vitamins, dietarysupplements, tonics/bottled nutritive drinks, child-specific vitamins,dietary supplements, any other products of or relating to or providingnutrition, and combinations thereof. Topical analgesics and/oranesthetic include any topical creams/ointments/gels used to alleviatesuperficial or deep-seated aches and pains, e.g. muscle pain; teethinggel; patches with analgesic ingredient; and combinations thereof. Cough,cold and allergy remedies include, but are not limited to decongestants,cough remedies, pharyngeal preparations, medicated confectionery,antihistamines and child-specific cough, cold and allergy remedies; andcombination products. Antihistamines and/or allergy remedies include,but are not limited to any systemic treatments for hay fever, nasalallergies, insect bites and stings. Examples of oral hygiene productinclude, but are not limited to mouth cleaning strips, toothpaste,toothbrushes, mouthwashes/dental rinses, denture care, mouth freshenersat-home teeth whiteners and dental floss.

In another embodiment, the present compounds are added to food orbeverage products or formulations. Examples of food and beverageproducts or formulations include, but are not limited to sweet coatings,frostings, or glazes for comestible products or any entity included inthe Soup category, the Dried Processed Food category, the Beveragecategory, the Ready Meal category, the Canned or Preserved Foodcategory, the Frozen Processed Food category, the Chilled Processed Foodcategory, the Snack Food category, the Baked Goods category, theConfectionary category, the Dairy Product category, the Ice Creamcategory, the Meal Replacement category, the Pasta and Noodle category,and the Sauces, Dressings, Condiments category, the Baby Food category,and/or the Spreads category.

In general, the Soup category refers to canned/preserved, dehydrated,instant, chilled, UHT and frozen soup. For the purpose of thisdefinition soup(s) means a food prepared from meat, poultry, fish,vegetables, grains, fruit and other ingredients, cooked in a liquidwhich may include visible pieces of some or all of these ingredients. Itmay be clear (as a broth) or thick (as a chowder), smooth, pureed orchunky, ready-to-serve, semi-condensed or condensed and may be servedhot or cold, as a first course or as the main course of a meal or as abetween meal snack (sipped like a beverage). Soup may be used as aningredient for preparing other meal components and may range from broths(consommé) to sauces (cream or cheese-based soups).

“Dehydrated and Culinary Food Category” usually means: (i) Cooking aidproducts such as: powders, granules, pastes, concentrated liquidproducts, including concentrated bouillon, bouillon and bouillon likeproducts in pressed cubes, tablets or powder or granulated form, whichare sold separately as a finished product or as an ingredient within aproduct, sauces and recipe mixes (regardless of technology); (ii) Mealsolutions products such as: dehydrated and freeze dried soups, includingdehydrated soup mixes, dehydrated instant soups, dehydratedready-to-cook soups, dehydrated or ambient preparations of ready-madedishes, meals and single serve entrees including pasta, potato and ricedishes; and (iii) Meal embellishment products such as: condiments,marinades, salad dressings, salad toppings, dips, breading, battermixes, shelf stable spreads, barbecue sauces, liquid recipe mixes,concentrates, sauces or sauce mixes, including recipe mixes for salad,sold as a finished product or as an ingredient within a product, whetherdehydrated, liquid or frozen.

The Beverage category usually means beverages, beverage mixes andconcentrates, including but not limited to, carbonated andnon-carbonated beverages, alcoholic and non-alcoholic beverages, readyto drink beverages, liquid concentrate formulations for preparingbeverages such as sodas, and dry powdered beverage precursor mixes. TheBeverage category also includes the alcoholic drinks, the soft drinks,sports drinks, isotonic beverages, and hot drinks. The alcoholic drinksinclude, but are not limited to beer, cider/perry, FABs, wine, andspirits. The soft drinks include, but are not limited to carbonates,such as colas and non-cola carbonates; fruit juice, such as juice,nectars, juice drinks and fruit flavored drinks; bottled water, whichincludes sparkling water, spring water and purified/table water;functional drinks, which can be carbonated or still and include sport,energy or elixir drinks; concentrates, such as liquid and powderconcentrates in ready to drink measure. The drinks, either hot or cold,include, but are not limited to coffee or ice coffee, such as fresh,instant, and combined coffee; tea or ice tea, such as black, green,white, oolong, and flavored tea; and other drinks including flavor-,malt- or plant-based powders, granules, blocks or tablets mixed withmilk or water.

The Snack Food category generally refers to any food that can be a lightinformal meal including, but not limited to Sweet and savory snacks andsnack bars. Examples of snack food include, but are not limited to fruitsnacks, chips/crisps, extruded snacks, tortilla/corn chips, popcorn,pretzels, nuts and other sweet and savory snacks. Examples of snack barsinclude, but are not limited to granola/muesli bars, breakfast bars,energy bars, fruit bars and other snack bars.

The Baked Goods category generally refers to any edible product theprocess of preparing which involves exposure to heat or excessivesunlight. Examples of baked goods include, but are not limited to bread,buns, cookies, muffins, cereal, toaster pastries, pastries, waffles,tortillas, biscuits, pies, bagels, tarts, quiches, cake, any bakedfoods, and any combination thereof.

The Ice Cream category generally refers to frozen dessert containingcream and sugar and flavoring. Examples of ice cream include, but arenot limited to: impulse ice cream; take-home ice cream; frozen yoghurtand artisanal ice cream; soy, oat, bean (e.g., red bean and mung bean),and rice-based ice creams.

The Confectionary category generally refers to edible product that issweet to the taste. Examples of confectionery include, but are notlimited to candies, gelatins, chocolate confectionery, sugarconfectionery, gum, and the likes and any combination products. The MealReplacement category generally refers to any food intended to replacethe normal meals, particularly for people having health or fitnessconcerns. Examples of meal replacement include, but are not limited toslimming products and convalescence products.

The Ready Meal category generally refers to any food that can be servedas meal without extensive preparation or processing. The ready mealincludes products that have had recipe “skills” added to them by themanufacturer, resulting in a high degree of readiness, completion andconvenience. Examples of ready meal include, but are not limited tocanned/preserved, frozen, dried, chilled ready meals; dinner mixes;frozen pizza; chilled pizza; and prepared salads.

The Pasta and Noodle category includes any pastas and/or noodlesincluding, but not limited to canned, dried and chilled/fresh pasta; andplain, instant, chilled, frozen and snack noodles.

The Canned/Preserved Food category includes, but is not limited tocanned/preserved meat and meat products, fish/seafood, vegetables,tomatoes, beans, fruit, ready meals, soup, pasta, and othercanned/preserved foods.

The Frozen Processed Food category includes, but is not limited tofrozen processed red meat, processed poultry, processed fish/seafood,processed vegetables, meat substitutes, processed potatoes, bakeryproducts, desserts, ready meals, pizza, soup, noodles, and other frozenfood.

The Dried Processed Food category includes, but is not limited to rice,dessert mixes, dried ready meals, dehydrated soup, instant soup, driedpasta, plain noodles, and instant noodles.

The Chill Processed Food category includes, but is not limited tochilled processed meats, processed fish/seafood products, lunch kits,fresh cut fruits, ready meals, pizza, prepared salads, soup, fresh pastaand noodles.

The Sauces, Dressings and Condiments category includes, but is notlimited to tomato pastes and purees, bouillon/stock cubes, herbs andspices, monosodium glutamate (MSG), table sauces, soy based sauces,pasta sauces, wet/cooking sauces, dry sauces/powder mixes, ketchup,mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickledproducts, and other sauces, dressings and condiments.

The Baby Food category includes, but is note limited to milk- orsoybean-based formula; and prepared, dried and other baby food.

The Spreads category includes, but is not limited to jams and preserves,honey, chocolate spreads, nut based spreads, and yeast based spreads.

The Dairy Product category generally refers to edible product producedfrom mammal's milk. Examples of dairy product include, but are notlimited to drinking milk products, cheese, yoghurt and sour milk drinks,and other dairy products.

Additional examples for comestible composition, particularly food andbeverage products or formulations, are provided as follows. Exemplarycomestible compositions include one or more confectioneries, chocolateconfectionery, tablets, countlines, bagged selflines/softlines, boxedassortments, standard boxed assortments, twist wrapped miniatures,seasonal chocolate, chocolate with toys, alfajores, other chocolateconfectionery, mints, standard mints, power mints, boiled sweets,pastilles, gums, jellies and chews, toffees, caramels and nougat,medicated confectionery, lollipops, liquorice, other sugarconfectionery, gum, chewing gum, sugarized gum, sugar-free gum,functional gum, bubble gum, bread, packaged/industrial bread,unpackaged/artisanal bread, pastries, cakes, packaged/industrial cakes,unpackaged/artisanal cakes, cookies, chocolate coated biscuits, sandwichbiscuits, filled biscuits, savory biscuits and crackers, breadsubstitutes, breakfast cereals, rte cereals, family breakfast cereals,flakes, muesli, other cereals, children's breakfast cereals, hotcereals, ice cream, impulse ice cream, single portion dairy ice cream,single portion water ice cream, multi-pack dairy ice cream, multi-packwater ice cream, take-home ice cream, take-home dairy ice cream, icecream desserts, bulk ice cream, take-home water ice cream, frozenyoghurt, artisanal ice cream, dairy products, milk, fresh/pasteurizedmilk, full fat fresh/pasteurized milk, semi skimmed fresh/pasteurizedmilk, long-life/uht milk, full fat long life/uht milk, semi skimmed longlife/uht milk, fat-free long life/uht milk, goat milk,condensed/evaporated milk, plain condensed/evaporated milk, flavored,functional and other condensed milk, flavored milk drinks, dairy onlyflavored milk drinks, flavored milk drinks with fruit juice, soy milk,sour milk drinks, fermented dairy drinks, coffee whiteners, powder milk,flavored powder milk drinks, cream, cheese, processed cheese, spreadableprocessed cheese, unspreadable processed cheese, unprocessed cheese,spreadable unprocessed cheese, hard cheese, packaged hard cheese,unpackaged hard cheese, yoghurt, plain/natural yoghurt, flavoredyoghurt, fruited yoghurt, probiotic yoghurt, drinking yoghurt, regulardrinking yoghurt, probiotic drinking yoghurt, chilled and shelf-stabledesserts, dairy-based desserts, soy-based desserts, chilled snacks,fromage frais and quark, plain fromage frais and quark, flavored fromagefrais and quark, savory fromage frais and quark, sweet and savorysnacks, fruit snacks, chips/crisps, extruded snacks, tortilla/cornchips, popcorn, pretzels, nuts, other sweet and savory snacks, snackbars, granola bars, breakfast bars, energy bars, fruit bars, other snackbars, meal replacement products, slimming products, convalescencedrinks, ready meals, canned ready meals, frozen ready meals, dried readymeals, chilled ready meals, dinner mixes, frozen pizza, chilled pizza,soup, canned soup, dehydrated soup, instant soup, chilled soup, hotsoup, frozen soup, pasta, canned pasta, dried pasta, chilled/freshpasta, noodles, plain noodles, instant noodles, cups/bowl instantnoodles, pouch instant noodles, chilled noodles, snack noodles, cannedfood, canned meat and meat products, canned fish/seafood, cannedvegetables, canned tomatoes, canned beans, canned fruit, canned readymeals, canned soup, canned pasta, other canned foods, frozen food,frozen processed red meat, frozen processed poultry, frozen processedfish/seafood, frozen processed vegetables, frozen meat substitutes,frozen potatoes, oven baked potato chips, other oven baked potatoproducts, non-oven frozen potatoes, frozen bakery products, frozendesserts, frozen ready meals, frozen pizza, frozen soup, frozen noodles,other frozen food, dried food, dessert mixes, dried ready meals,dehydrated soup, instant soup, dried pasta, plain noodles, instantnoodles, cups/bowl instant noodles, pouch instant noodles, chilled food,chilled processed meats, chilled fish/seafood products, chilledprocessed fish, chilled coated fish, chilled smoked fish, chilled lunchkit, chilled ready meals, chilled pizza, chilled soup, chilled/freshpasta, chilled noodles, oils and fats, olive oil, vegetable and seedoil, cooking fats, butter, margarine, spreadable oils and fats,functional spreadable oils and fats, sauces, dressings and condiments,tomato pastes and purees, bouillon/stock cubes, stock cubes, gravygranules, liquid stocks and fonds, herbs and spices, fermented sauces,soy based sauces, pasta sauces, wet sauces, dry sauces/powder mixes,ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings,regular salad dressings, low fat salad dressings, vinaigrettes, dips,pickled products, other sauces, dressings and condiments, baby food,milk formula, standard milk formula, follow-on milk formula, toddlermilk formula, hypoallergenic milk formula, prepared baby food, driedbaby food, other baby food, spreads, jams and preserves, honey,chocolate spreads, nut-based spreads, and yeast-based spreads. Exemplarycomestible compositions also include confectioneries, bakery products,ice creams, dairy products, sweet and savory snacks, snack bars, mealreplacement products, ready meals, soups, pastas, noodles, canned foods,frozen foods, dried foods, chilled foods, oils and fats, baby foods, orspreads or a mixture thereof. Exemplary comestible compositions alsoinclude breakfast cereals, sweet beverages or solid or liquidconcentrate compositions for preparing beverages, ideally so as toenable the reduction in concentration of previously known saccharidesweeteners, or artificial sweeteners.

Typically at least a sweet receptor modulating amount, a sweet receptorligand modulating amount, a sweet flavor modulating amount, a sweetflavoring agent amount, or a sweet flavor enhancing amount of one ormore of the present compounds will be added to the ingestiblecomposition, optionally in the presence of known sweeteners, e.g., sothat the sweet flavor modified ingestible composition has an increasedsweet taste as compared to the ingestible composition prepared withoutthe compounds of the present invention, as judged by human beings oranimals in general, or in the case of formulations testing, as judged bya majority of a panel of at least eight human taste testers, viaprocedures commonly known in the field.

The concentration of sweet flavoring agent needed to modulate or improvethe flavor of the ingestible composition will of course depend on manyvariables, including the specific type of the ingestible composition andits various other ingredients, especially the presence of other knownsweet flavoring agents and the concentrations thereof, the naturalgenetic variability and individual preferences and health conditions ofvarious human beings tasting the compositions, and the subjective effectof the particular compound on the taste of such chemosensory compounds.

One application of the present compounds is for modulating (inducing,enhancing or inhibiting) the sweet taste or other taste properties ofother natural or synthetic sweet tastants, and ingestible compositionsmade therefrom. In one embodiment, the compounds of the presentinvention is used or provided in its ligand enhancing concentration(s).For example, a broad but also low range of concentrations of thecompounds or entities of the present invention would typically berequired, i.e., from about 0.001 ppm to 100 ppm, or narrower alternativeranges from about 0.1 ppm to about 10 ppm, from about 0.01 ppm to about30 ppm, from about 0.05 ppm to about 10 ppm, from about 0.01 ppm toabout 5 ppm, or from about 0.02 ppm to about 2 ppm, or from about 0.01ppm to about 1 ppm.

In one embodiment, the present invention provides a sweet enhancingcomposition. The sweet enhancing composition comprises a compound of thepresent invention in an amount effective to provide sweetening, e.g.,sweet flavor enhancing amount in combination with a first amount ofsweetener, wherein the sweetening is more than the sweetening providedby the first amount of sweetener without the compound.

In one embodiment, the present invention provides an ingestiblecomposition which comprises the sweet enhancing composition of thepresent invention. In certain embodiments, the present ingestiblecomposition is in the form of a food or beverage product, apharmaceutical composition, a nutritional product, a dietary supplement,over-the-counter medication, or oral care product.

In one embodiment, the present invention provides a sweetenerreplacement composition which comprises one or more compounds of thepresent invention in an amount effective to provide sweetening, e.g., ata concentration higher than their ligand enhancing concentration in theabsence of a sweetener, e.g., sucrose other than the presentcompound(s).

According to another aspect of the invention, the compounds of thepresent invention are provided in a flavoring concentrate formulation,e.g., suitable for subsequent processing to produce a ready-to-use(i.e., ready-to-serve) product. By “a flavoring concentrateformulation”, it is meant a formulation which should be reconstitutedwith one or more diluting medium to become a ready-to-use composition.The term “ready-to-use composition” is used herein interchangeably with“ingestible composition”, which denotes any substance that, either aloneor together with another substance, can be taken by mouth whetherintended for consumption or not. In one embodiment, the ready-to-usecomposition includes a composition that can be directly consumed by ahuman or animal. The flavoring concentrate formulation is typically usedby mixing with or diluted by one or more diluting medium, e.g., anyconsumable or ingestible ingredient or product, to impart or modify oneor more flavors to the diluting medium. Such a use process is oftenreferred to as reconstitution. The reconstitution can be conducted in ahousehold setting or an industrial setting. For example, a frozen fruitjuice concentrate can be reconstituted with water or other aqueousmedium by a consumer in a kitchen to obtain the ready-to-use fruit juicebeverage. In another example, a soft drink syrup concentrate can bereconstituted with water or other aqueous medium by a manufacture inlarge industrial scales to produce the ready-to-use soft drinks. Sincethe flavoring concentrate formulation has the flavoring agent or flavormodifying agent in a concentration higher than the ready-to-usecomposition, the flavoring concentrate formulation is typically notsuitable for being consumed directly without reconstitution. There aremany benefits of using and producing a flavoring concentrateformulation. For example, one benefit is the reduction in weight andvolume for transportation as the flavoring concentrate formulation canbe reconstituted at the time of usage by the addition of suitablesolvent, solid or liquid.

In one embodiment, the flavoring concentrate formulation comprises i) asflavor modifying ingredient, a compound of the present invention; ii) acarrier; and iii) optionally at least one adjuvant. The term “as flavormodifying ingredient” denotes that the compound of the present inventionacts as a flavoring agent or a flavor modifying agent (such as a flavorenhancer) in the formulation. The term “carrier” denotes a usuallyinactive accessory substance, such as solvents, binders, or other inertmedium, which is used in combination with the present compound and oneor more optional adjuvants to form the formulation. For example, wateror starch can be a carrier for a flavoring concentrate formulation. Insome embodiments, the carrier is the same as the diluting medium forreconstituting the flavoring concentrate formulation; and in otherembodiments, the carrier is different from the diluting medium. The term“carrier” as used herein includes, but is not limited to, ingestiblyacceptable carrier.

The term “adjuvant” denotes an additive which supplements, stabilizes,maintains, or enhances the intended function or effectiveness of theactive ingredient, such as the compound of the present invention. In oneembodiment, the at least one adjuvant comprises one or more flavoringagents. The flavoring agent may be of any flavor known to one skilled inthe art or consumers, such as the flavor of chocolate, coffee, tea,mocha, French vanilla, peanut butter, chai, or combinations thereof. Inanother embodiment, the at least one adjuvant comprises one or moresweeteners. The one or more sweeteners can be any of the sweetenersdescribed in this application. In another embodiment, the at least oneadjuvant comprises one or more ingredients selected from the groupconsisting of a emulsifier, a stabilizer, an antimicrobial preservative,an antioxidant, vitamins, minerals, fats, starches, protein concentratesand isolates, salts, and combinations thereof. Examples of emulsifiers,stabilizers, antimicrobial preservatives, antioxidants, vitamins,minerals, fats, starches, protein concentrates and isolates, and saltsare described in U.S. Pat. No. 6,468,576, the contents of which arehereby incorporated by reference in its entirety for all purposes.

In one embodiment, the present flavoring concentrate formulation can bein a form selected from the group consisting of liquid includingsolution and suspension, solid, foamy material, paste, gel, cream, and acombination thereof, such as a liquid containing certain amount of solidcontents. In one embodiment, the flavoring concentrate formulation is inform of a liquid including aqueous-based and nonaqueous-based. Thepresent flavoring concentrate formulation can be carbonated ornon-carbonated.

The flavoring concentrate formulation may further comprise a freezingpoint depressant, nucleating agent, or both as the at least oneadjuvant. The freezing point depressant is a ingestibly acceptablecompound or agent which can depress the freezing point of a liquid orsolvent to which the compound or agent is added. That is, a liquid orsolution containing the freezing point depressant has a lower freezingpoint than the liquid or solvent without the freezing point depressant.In addition to depress the onset freezing point, the freezing pointdepressant may also lower the water activity of the flavoringconcentrate formulation. The examples of the freezing point depressantinclude, but are not limited to, carbohydrates, oils, ethyl alcohol,polyol, e.g., glycerol, and combinations thereof. The nucleating agentdenotes a ingestibly acceptable compound or agent which is able tofacilitate nucleation. The presence of nucleating agent in the flavoringconcentrate formulation can improve the mouthfeel of the frozen slushesof a frozen slush and to help maintain the physical properties andperformance of the slush at freezing temperatures by increasing thenumber of desirable ice crystallization centers. Examples of nucleatingagents include, but are not limited to, calcium silicate, calciumcarbonate, titanium dioxide, and combinations thereof.

In one embodiment, the flavoring concentrate formulation is formulatedto have a low water activity for extended shelf life. Water activity isthe ratio of the vapor pressure of water in a formulation to the vaporpressure of pure water at the same temperature. In one embodiment, theflavoring concentrate formulation has a water activity of less thanabout 0.85. In another embodiment, the flavoring concentrate formulationhas a water activity of less than about 0.80. In another embodiment, theflavoring concentrate formulation has a water activity of less thanabout 0.75.

In one embodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 2 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 5 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 10 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 15 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 20 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 30 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 40 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 50 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is at least 60 times of theconcentration of the compound in a ready-to-use composition. In oneembodiment, the flavoring concentrate formulation has the presentcompound in a concentration that is up to 100 times of the concentrationof the compound in a ready-to-use composition.

Preparations

The starting materials used in preparing the compounds of the invention,i.e. the various structural subclasses and species of the compounds ofthe synthetic precursors of the present compounds of Formula (I), areoften known compounds, or can be synthesized by known methods describedin the literature, or are commercially available from various sourceswell known to those of ordinary skill in the art, such as for example,Sigma-Aldrich Corporation of St. Louis, Mo. USA and their subsidiariesFluka and Riedel-de Haen, at their various other worldwide offices, andother well known chemical suppliers such as Fisher Scientific, TCIAmerica of Philadelphia, Pa., ChemDiv of San Diego, Calif., Chembridgeof San Diego, Calif., Asinex of Moscow, Russia, SPECS/BIOSPECS of theNetherlands, Maybridge of Cornwall, England, Acros, TimTec of Russia,Comgenex of South San Francisco, Calif., and ASDI Biosciences of Newark,Del.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out the synthesis of many starting materialsand subsequent manipulations without further direction, that is, it iswell within the scope and practice of the skilled artisan to carry outmany desired manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification, saponification, nitrations,hydrogenations, reductive animation and the like. These manipulationsare discussed in standard texts such as March's Advanced OrganicChemistry (3d Edition, 1985, Wiley-Interscience, New York), Feiser andFeiser's Reagents for Organic Synthesis, and in the various volumes andeditions oïMethoden der Organischen Chemie (Houben-Weyl), and the like.Many general methods for preparation of starting materials comprisingvariously substituted heterocyclic, heteroaryl, and aryl rings (theprecursors of Ar, hAr¹, and/or hAr²) can be found in Methoden derOrganischen Chemie (Houben-Weyl), whose various volumes and editions areavailable from Georg Thieme Verlag, Stuttgart. The entire disclosures ofthe treatises recited above are hereby incorporated by reference intheir entireties for their teachings regarding methods for synthesizingorganic compounds and their precursors.

The skilled artisan will also readily appreciate that certain reactionsare best carried out when other functionality is masked or protected inthe molecule, thus avoiding any undesirable side reactions and/orincreasing the yield of the reaction. Often the skilled artisan utilizesprotecting groups to accomplish such increased yields or to avoid theundesired reactions. These reactions are found in the literature and arealso well within the scope of the skilled artisan. Examples of many ofthese manipulations can be found for example in T. Greene and P. Wuts,Protecting Groups in Organic Synthesis, 3^(r) Ed., John Wiley & Sons(1999).

Some exemplary synthetic methods for preparing the present compounds areillustrated in the Schemes 1 to 4 below.

As shown in Scheme 1, substituted 4-aminoquinoline-3-carboxylatederivatives (VI) can be prepared by reacting the corresponding anilinesI with 2-(alkoxymethylene)malonates II followed by cyclization of theintermediates III under elevated temperature to provide the hydroxylintermediates IV that can be treated with POCl₃ or SO₂Cl₂ to provide thecorresponding chloride derivatives V that can be further treated withammonia or amines to give the desired amino-quinolines VI. (Kamal, A. etal. Bioorg. Med. Chem. 2005, 13, 2021-2029; Fryer, R. I. et al. J. Med.Chem. 1993, 36, 1669-1673; Bi, Y. et al. Bioorg. Med. Chem. Lett. 2004,14, 1577-1580; Li, S. Y. et al. Bioorg. Med. Chem. 2006, 14, 7370-7376.Koga, H. et al. J. Med. Chem. 1980, 23, 1358-1363.).

Substituted 4-aminoquinoline-3-carboxylate derivatives (VI) can also beprepared by reacting the corresponding 2-aminobenzoic acids VIII withphosgene or equivalent to provide the isatoic anhydrides IX that can befurther reacted with X to give the derivatives IV (Mai, A. et al. J.Med. Chem. 2006, 49, 6897-6907. Beutner, G. L. et al. J. Org. Chem.2007, 72, 7058-7061, and references cited therein.), which can beconverted to VI as described in Scheme 1.

Alternatively, substituted 4-aminoquinoline-3-carboxylate derivatives(VI) can be prepared by reacting the corresponding amino benzonitrilesXI with X to provide the amino derivatives XII (Sestili, I. et al. Eur.J. Med. Chem. 2004, 39, 1047-1057. Doucet-Personeni, C. et al. J. Med.Chem. 2001, 44, 3203-3215. Veronese, A. C. et al. Tetrahedron 1995, 51,12277-12284, and the references cited therein.) that can be furtheralkylated to give the substituted aminoquinolines VI as shown in Scheme3. Amino quinolines XII can also be prepared via a Michael addition ofthe 2-amino benzonitriles XI to various α,β-unsaturated carboxylatederivatives XIII, XIV or XV to provide the adducts XVI (MacNab, H. etal. Synthesis 2009, 2171-2174. Vicario, J. L. Synthesis 2007, 2065-2092,and references cited therein.) that can be further cyclized to give theamino quinolines XII (Han, G. F. et al. Synth. Commun. 2009, 39,2492-2505. Tabarrini, O. et al. Bioorg. Med. Chem. 2001, 9, 2921-2928.Shutske, G. M. et al. J. Med. Chem. 1989, 32, 1805-1813, and referencescited therein.).

As described in Scheme 4, hydrolysis of 4-aminoquinoline-3-carboxylatederivatives VI or XII in the presence of NaOH provide4-aminoquinoline-3-carboxylic acids XVII (Zhao, Y. L. et al. Eur. J.Med. Chem. 2005, 40, 792-797.) which can be further coupled with aminesXXII under standard conditions to give 4-aminoquinoline-3-carboxamidederivatives XVIII. When R³ and/or R⁴=H, 4-aminoquinoline-3-carboxylatesVI or XII can be further functionalized by coupling with acids XXIII togive 4-carboxamidoquinoline-3-carboxylates XIX. Compound XIX can befurther hydrolyzed to the acids XX that can be further coupled to theamines XXII to provide amide derivatives XXI.

EXAMPLES

Having now generally described the invention, the same will be morereadily understood by reference to the following examples, which areprovided by way of illustration and are not intended as limiting. It isunderstood that various modifications and changes can be made to theherein disclosed exemplary embodiments without departing from the spiritand scope of the invention.

Example 1 4-amino-6-methoxyquinoline-3-carboxylic acid

To a stirred solution of ethyl 4-amino-6-methoxyquinoline-3-carboxylate(Example 1a, 1.23 g, 5.0 mmol) in EtOH (20.0 mL) was added aqueous NaOH(2.0 N, 5.0 mL) at room temperature. The reaction mixture was thenrefluxed for 3 hr. The solution was then filtered and washed with water.The filtrate was cooled to 0° C. and neutralized carefully with 1 N HClto pH 7. Most of the EtOH was removed under reduced pressure, and theprecipitate was collected by filtration, washed with cold water, anddried under vacuum to give the title compound as an off-white solid(1.01 g, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.89 (s, 3H), 7.40 (dd,J=2.8, 9.4 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 8.77(s, 1H). MS 219 (MH⁺).

Example 1a ethyl 4-amino-6-methoxyquinoline-3-carboxylate

A mixture of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (Example1b, 796 mg, 3.0 mmol) and ammonia (25% aqueous solution, 10 mL) inisopropanol (40 mL) was stirred at 110° C. in a pressure reactorovernight. Most of the solvent was then removed under reduced pressure,and the reaction mixture was diluted with water. The precipitate wascollected by filtration, washed with cold water, and dried under vacuumto give the title compound as an off-white solid (680 mg, 92%). ¹H NMR(400 MHz, DMSO-d₆) δ 1.33 (t, J=7.0 Hz, 3H), 3.88 (s, 3H), 4.32 (q,J=7.0 Hz, 2H), 7.36 (dd, J=2.8, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H),7.74 (d, J=2.8 Hz, 1H), 8.23 (bs, 2H), 8.77 (s, 1H). MS 247 (MH⁺).

Example 1b ethyl 4-chloro-6-methoxyquinoline-3-carboxylate

A solution of ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (Example1c, 1.24 g, 5.0 mmol) in POCl₃ was refluxed under nitrogen for 3 hrs.The solution was cooled to room temperature and evaporated under reducedpressure. The residue was carefully quenched with ice, and neutralizedwith 2.0 N NaOH to pH 7. The precipitate was collected by filtration,washed with cold water, and dried under vacuum to give the titlecompound as a pale-yellow solid (1.29 g, 97%). ¹H NMR (400 MHz, DMSO-d₆)δ 1.36 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 7.57 (d,J=2.8 Hz, 1H), 7.61 (dd, J=2.8, 8.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H),8.97 (s, 1H). MS 266, 268 (MH⁺).

Example 1c ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate

A mixture of 4-methoxyaniline (12.3 g, 100 mmol) and diethyl2-(ethoxymethylene)malonate (21.6 g, 100 mmol) was stirred at 120° C.under nitrogen for 4 hrs. The solution was cooled to room temperatureand Ph₂O (100 mL) was added. The reaction mixture was refluxed at 260°C. under nitrogen for 8 hrs. The solution was cooled to room temperatureand diluted with hexanes. The resultant precipitate was collected byfiltration, washed with 25% ethyl acetate in hexanes, and dried undervacuum to give ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate as apale-yellow solid (4.21 g, 17%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.26 (t,J=7.0 Hz, 3H), 3.83 (s, 3H), 4.19 (q, J=7.0 Hz, 2H), 7.32 (dd, J=3.2,9.6 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.56 (d, J=9.6 Hz, 1H), 8.47 (s,1H), 12.27 (s, 1H). MS 248 (MH⁺).

Example 24-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)-propoxy)-2-methylquinoline-3-carboxylate(Example 2a) as an off-white solid (41%). ¹H NMR (400 MHz, DMSO-d₆) δ0.73 (t, J=7.6 Hz, 3H), 1.25 (s, 6H), 1.33-1.42 (m, 2H), 2.76 (s, 3H),3.00-3.05 (m, 2H), 4.16 (s, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.89 (t, J=5.8 Hz, 1H), 8.85 (bs, 1H),12.28 (bs, 1H), 12.78 (bs, 1H). MS 360 (MH⁺).

Example 2a ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-methylquinoline-3-carboxylate

To a solution of3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropan-amide (Tachdjian,C. et al. PCT Int. Appl. 2008, WO 2008154221, 1.38 g, 5.0 mmol) andethyl acetoacetate (0.66 g, 5.0 mmol) in dry toluene (150 mL) was addedSnCl₄ (2.61 g, 10.0 mmol) dropwise via syringe at room temperature undernitrogen. After 1 hr at room temperature, the reaction mixture wasrefluxed for an additional 5 hrs. The solution was cooled to roomtemperature and the solvent removed under reduced pressure. The residuewas diluted with EtOAc, and aqueous NaOH (2N) was added at roomtemperature to pH>8. The solution was filtered and the organic layerseparated. The aqueous layer was extracted with EtOAc (5×). The combinedorganic layers was washed with brine, and dried over Na₂SO₄. Afterevaporation of the solvent, the residue was purified by chromatographyon silica gel (0.5% MeOH in EtOAc) to give the title compound as anoff-white solid (1.63 g, 84%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.73 (t,J=7.6 Hz, 3H), 1.25 (s, 6H), 1.32 (t, J=7.4 Hz, 3H), 1.35-1.42 (m, 2H),2.54 (s, 3H), 3.00-3.05 (m, 2H), 4.12 (s, 2H), 4.31 (q, J=7.4 Hz, 2H),6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H),7.80 (t, J=5.6 Hz, 1H), 8.08 (s, 2H). MS 388 (MH⁺).

Example 3 4-amino-6-methoxy-2-methylquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-6-methoxy-2-methylquinoline-3-carboxylate (Example 3a) as awhite solid (87%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.83 (s, 3H), 3.90 (s,3H), 7.57 (dd, J=2.4, 8.2 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.10 (d,J=2.4 Hz, 1H), 9.39 (s, 1H), 9.67 (s, 1H). MS 233 (MH⁺).

Example 3a ethyl 4-amino-6-methoxy-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-5-methoxybenzonitrile (Campbell,J. B. et al. Synth. Commun. 1989, 19, 2255-2263.) and ethyl acetoacetateas an off-white solid (92%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.33 (t, J=6.8Hz, 3H), 2.57 (s, 3H), 3.86 (s, 3H), 4.33 (q, J=6.8 Hz, 2H), 7.28 (dd,J=2.8, 9.2 Hz, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.60 (bs, 2H), 7.63 (d,J=2.8 Hz, 1H). MS 261 (MH⁺).

Example 4 4-amino-2-phenylquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-2-phenylquinoline-3-carboxylate (Example 4a) as an off-whitesolid (33%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.39-7.52 (m, 7H), 7.79 (m,3H), 8.33 (d, J=8.0 Hz, 1H), 12.63 (bs, 1H). MS 265 (MH⁺).

Example 4a ethyl 4-amino-2-phenylquinoline-3-carboxylate

Prepared as in Example 2a from 2-aminobenzonitrile and ethyl3-oxo-3-phenylpropanoate as a yellow solid (45%). ¹H NMR (400 MHz,DMSO-d₆) δ 0.72 (t, J=8.0 Hz, 3H), 3.92 (q, J=8.0 Hz, 2H), 7.44 (m, 5H),7.50 (m, 1H), 7.61 (bs, 2H), 7.73 (m, 1H), 7.83 (d, J=8.0 Hz, 1H), 8.37(d, J=8.0 Hz, 1H). MS 293 (MH⁺).

Example 5 4-amino-2-ethylquinoline-3-carboxylic acid

Prepared as in Example 2 from methyl4-amino-2-ethylquinoline-3-carboxylate (Example 5a) as a white solid(26%). ¹H NMR (400 MHz, DMSO-d₆+1 drop D₂O) δ 1.24 (t, J=8.0 Hz, 3H),3.28 (q, J=8.0 Hz, 2H), 7.56 (t, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H),7.83 (t, J=8.0 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H).). MS 217 (MH⁺).

Example 5a ethyl 4-amino-2-phenylquinoline-3-carboxylate

Prepared as in Example 2a from 2-aminobenzonitrile and methyl3-oxopentanoate as a solid (27%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.18 (t,J=8.0 Hz, 3H), 2.88 (q, J=8.0 Hz, 2H), 3.86 (s, 3H), 7.40 (m, 1H), 7.44(bs, 2H), 7.64 (m, 1H), 7.68 (m, 1H), 8.26 (d, J=8.0 Hz, 1H). MS 231(MH⁺).

Example 6 4-amino-2-methylquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-2-methylquinoline-3-carboxylate (Example 6a) as a off-whitesolid (41%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.05 (t, J=8.0 Hz, 3H), 2.84(s, 3H), 7.56 (bs, 1H), 7.76 (m, 1H), 7.82 (bs, 1H), 8.39 (d, J=8.0 Hz,1H), 8.99 (bs, 1H), 12.00 (bs, 1H), 12.98 (bs, 1H). MS 203 (MH⁺).

Example 6a ethyl 4-amino-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-aminobenzonitrile and ethyl3-oxobutanoate as a yellow solid (32%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.33(t, J=8.0 Hz, 3H), 2.61 (s, 3H), 4.34 (q, J=8.0 Hz, 2H), 7.41 (m, 1H),7.66 (m, 2H), 7.74 (bs, 2H), 8.27 (d, J=8.0 Hz, 1H). MS 231 (MH⁺).

Example 74-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-ethyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from methyl4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-ethylquinoline-3-carboxylate(Example 7a) as a solid (75%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.75 (t,J=8.0 Hz, 3H), 1.03 (t, J=8.0 Hz, 3H), 1.27 (s, 6H), 1.39 (m, 2H), 3.04(q, J=4.0 Hz, 2H), 3.45 (q, J=4.0 Hz, 2H), 4.17 (s, 2H), 7.04 (d, J=8.0Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.90 (t, J=4.0Hz, 1H), 8.89 (bs, 1H), 12.75 (bs, 1H). MS 374 (MH⁺).

Example 7a methyl4-amino-5-(2,2-dimethyl-3-oxo-3-(propylamino)propoxy)-2-ethylquinoline-3-carboxylate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropan-amide (Tachdjian,C. et al. PCT Int. Appl. 2008, WO 2008154221) and methyl 3-oxopentanoateas a yellow solid (17%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.75 (t, J=8.0 Hz,3H), 1.17 (t, J=8.0 Hz, 3H), 1.26 (s, 6H), 1.40 (m, 2H), 2.84 (q, J=8.0Hz, 2H), 3.04 (q, J=8.0 Hz, 2H), 3.85 (s, 3H), 4.13 (s, 2H), 6.88 (d,J=8.0 Hz, 1H), 7.27 (dd, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.81 (m,3H). MS 388 (MH⁺).

Example 8 4-amino-6-phenoxyquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-6-phenoxyquinoline-3-carboxylate (Example 8a) as a off-whitesolid (50%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.07 (d, J=8.0 Hz, 2H), 7.16(t, J=8.0 Hz, 1H), 7.42 (m, 2H), 7.49 (dd, J=8.0 Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 8.13 (d, J=4.0 Hz, 1H), 8.86 (s, 1H). MS 281 (MH⁺).

Example 8a ethyl 4-amino-6-phenoxyquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-6-phenoxyquinoline-3-carboxylate (Example 8b) and ammonia as aoff-white solid (82%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.35 (t, J=8.0 Hz,3H), 4.35 (q, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 7.15 (t, J=8.0 Hz,1H), 7.40 (m, d, 2H), 7.46 (dd, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H),8.13 (d, J=4.0 Hz, 1H), 8.27 (bs, 2H), 8.87 (s, 1H). MS 309 (MH⁺).

Example 8b ethyl 4-chloro-6-phenoxyquinoline-3-carboxylate

Prepared as in Example 1b from ethyl4-hydroxy-6-phenoxyquinoline-3-carboxylate (Example 8c) and POCl₃ as atan solid (96%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (t, J=8.0 Hz, 3H),4.40 (q, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.29 (t, J=8.0 Hz, 1H),7.50 (t, J=8.0 Hz, 2H), 7.63 (d, J=4.0 Hz, 1H), 7.76 (dd, J=8.0 Hz, 1H),8.21 (d, J=8.0 Hz, 1H), 9.06 (s, 1H). MS 328, 330 (MH⁺).

Example 8c ethyl 4-hydroxy-6-phenoxyquinoline-3-carboxylate

Prepared as in Example 1c from 4-phenoxyaniline and diethyl2-(ethoxymethylene)malonate as a white solid (41%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.24 (t, J=8.0 Hz, 3H), 4.18 (q, J=8.0 Hz, 2H), 7.07 (d,J=8.0 Hz, 2H), 7.20 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.47 (m,2H), 7.69 (d, J=12.0 Hz, 1H), 12.39 (bs, 1H). MS 310 (MH⁺).

Example 9 4-amino-7-fluoroquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-7-fluoroquinoline-3-carboxylate (Example 9a) as an off whitesolid (66%). ¹H NMR (CD₃OD, 400 MHz) δ □ 07.49 (m, 2H), 8.50 (dd,J=10.0, 5.2 Hz, 1H), 8.94 (s, 1H). MS 207 (MH⁺).

Example 9a ethyl 4-amino-7-fluoroquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-7-fluoroquinoline-3-carboxylate (Example 9b) and ammonia as anoff white solid (99%). MS 235 (MH⁺).

Example 9b ethyl 4-chloro-7-fluoroquinoline-3-carboxylate

Prepared as in Example 1b from ethyl7-fluoro-4-hydroxyquinoline-3-carboxylate (Example 9c) and POCl₃ as anoff white solid (96%). MS 254, 256 (MH⁺).

Example 9c ethyl 7-fluoro-4-hydroxyquinoline-3-carboxylate

Prepared as in Example 1c from 3-fluoroaniline and diethyl2-(ethoxymethylene)malonate as a brown solid (51%). MS 236 (MH⁺).

Example 10 4-amino-6-isopropoxyquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-6-isopropoxyquinoline-3-carboxylate (Example 10a) as a an offwhite solid (94%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (s, 3H), 1.32 (s,3H), 4.82 (m, 1H), 7.37 (d, J=9.2 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.78(s, 1H), 8.75 (s, 1H). MS 247 (MH⁺).

Example 10a ethyl 4-amino-6-isopropoxyquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-6-isopropoxyquinoline-3-carboxylate (Example 10b) and ammoniaas an off white solid (75%). MS 275 (MH⁺).

Example 10b 4-chloro-6-isopropoxyquinoline-3-carboxylate

Prepared as in Example 1b from ethyl4-hydroxy-6-isopropoxyquinoline-3-carboxylate (Example 10c) and POCl₃ asa pale yellow solid (93%). MS 294, 296 (MH⁺).

Example 10c ethyl 4-hydroxy-6-isopropoxyquinoline-3-carboxylate

Prepared as in Example 1c from 4-isopropoxyaniline and diethyl2-(ethoxymethylene)malonate as a yellow solid (20%). MS 276 (MH⁺).

Example 11 4-amino-6-methoxy-2-methyl-1,5-naphthyridine-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-6-methoxy-2-methyl-1,5-naphthyridine-3-carboxylate (Example 11a)as an off white solid (56%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.68 (s, 3H),4.02 (s, 3H), 7.21 (d, J=8.8 Hz, 1H), 7.99 (d, J=9.2 Hz, 1H). MS 234(MH⁺).

Example 11a ethyl4-amino-6-methoxy-2-methyl-1,5-naphthyridine-3-carboxylate

Prepared as in Example 2a from 3-amino-6-methoxypicolinonitrile (Example11b) and ethyl 3-oxobutanoate as an off white solid (45%). MS 262 (MH⁺).

Example 11b 3-amino-6-methoxypicolinonitrile

To a solution of 6-methoxy-3-nitropicolinonitrile (Piersanti, G. et al.Org. Biomolecular Chem. 2007, 5, 2567-2571.) (2.0 g, 11.1 mmol) indiglyme (52 mL) was added dropwise a solution of SnCl₂ (6.35 g, 33.5mmol) in concentrated HCl solution (26 mL) at 0° C. The solution wasstirred at 0° C. for 1 hr, then the reaction mixture was neutralizedwith concentrated NaOH solution, and extracted with EtOAc (2×). Thecombined organic layers were washed with brine, and dried over Na₂SO₄.After evaporation of the solvent, the residue was purified bychromatography on silica gel (50% EtOAc in hexanes) to give3-amino-6-methoxypicolinonitrile (966 mg, 58%) as a brown solid. ¹H NMR(400 MHz, CDCl₃) δ 3.81 (s, 3H), 4.10 (bs, 2H), 6.81 (d, J=8.0 Hz, 1H),7.08 (d, J=8.0 Hz, 1H). MS 150 (MH⁺).

Example 12 4-amino-2,5-dimethylquinoline-3-carboxylic acid

Ethyl 4-(4-methoxybenzylamino)-2, 5-dimethylquinoline-3-carboxylate(Example 12a, 0.563 g, 1.54 mmol) was dissolved in TFA (8 mL) and theresultant solution was stirred at room temperature for 15 minutes, TFAwas then removed under vacuum to give the crude ethyl4-amino-2,5-dimethylquinoline-3-carboxylate product, which was dissolvedin EtOH (4 mL). To this solution was added NaOH (4.0 N, 3.86 mL) and thereaction mixture was stirred at 100° C. for 1 hr. Water (25 mL) wasadded, and the solvent was decanted away from insoluble material thenacidified with AcOH to pH 5.5. The precipitate was collected byfiltration to give the title compound (300 mg, 90%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 2.78 (s, 3H), 2.88 (s, 3H), 7.30 (d, J=7.2 Hz,1H), 7.58 (d, J=8.0 Hz, 1H), 7.65 (m, 1H), 7.8-8.0 (br, 1H), 12.2-12.9(br, 2H). MS 217 (MH⁺).

Example 12a ethyl4-(4-methoxybenzylamino)-2,5-dimethylquinoline-3-carboxylate

A solution of ethyl 4-chloro-2,5-dimethylquinoline-3-carboxylate(Example 12b, 0.518 g, 1.96 mmol) and (4-methoxyphenyl)methanamine (1.15mL, 8.86 mmol) in toluene (10 mL) and DMF (5 mL) were stirred at 115° C.under nitrogen for 12 hrs. The solvent was removed under vacuum, and theresidue was purified by chromatography on silica gel (0% to 50% EtOAc inhexanes) to give the title compound as an oil (563 mg, 79%). ¹H NMR (400MHz, DMSO-d₆) δ 1.24 (t, J=7.6 Hz, 3H), 2.45 (s, 3H), 2.78 (s, 3H), 3.73(s, 3H), 4.2-4.3 (m, 4H), 6.27 (t, J=6.0 Hz, 1H), 6.88 (d, J=8.4 Hz,2H), 7.19 (m, 3H), 7.48 (m, 1H), 7.58 (d, J=8.4 Hz, 1H). MS 365 (MH⁺).

Example 12b ethyl 4-chloro-2,5-dimethylquinoline-3-carboxylate

A solution of 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (Example 12c)(1.36 g, 7.68 mmol), ethyl 3-oxobutanoate (1.46 mL, 11.5 mmol), and NaOH(0.046 g, 1.15 mmol) in anhydrous dioxane (10 mL) were refluxed undernitrogen for 15 hrs. The solvent was then removed under vacuum, and theresidue was re-dissolved in DMF (15 mL). To this solution was addedPOCl₃ (1.41 mL, 15.4 mmol), and the reaction mixture was stirred at roomtemperature for 45 minutes. The reaction was carefully quenched with icewater (150 mL), and extracted with DCM (2×75 mL). The combined organiclayers were washed with brine, and dried over Na₂SO₄. After evaporationof the solvent, the residue was purified by chromatography on silica geleluting with 50% EtOAc in hexanes to give the title compound as red oil(520 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (t, J=7.6 Hz, 3H), 2.58(s, 3H), 2.97 (s, 3H), 4.46 (q, J=7.6 Hz, 2H), 7.51 (d, J=7.2 Hz, 1H),7.71 (m, 1H), 7.87 (d, J=7.6 Hz, 1H). MS 264, 266 (MH⁺).

Example 12c 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione

Trichloromethyl carbonochloridate (2.04 mL, 16.9 mmol) was added to2-amino-6-methylbenzoic acid (2.13 g, 14.1 mmol) in anhydrous dioxane(32 mL) under nitrogen, then refluxed for 30 minutes. Diethyl ether (100mL) was added, and the precipitated solid was collected by filtration togive 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (1.4 g, 56%) which wasused without further purification.

Example 13 4-amino-6-ethoxyquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-6-ethoxyquinoline-3-carboxylate (Example 13a) as an off whitesolid (76%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.39 (t, J=7.2 Hz, 3H), 4.18(q, J=7.2 Hz, 2H), 7.50-7.53 (m, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.95 (d,J=2.0 Hz, 1H), 8.86 (s, 1H), 9.26 (bs, 1H), 9.86 (bs, 1H). MS 233 (MH⁺).

Example 13a ethyl 4-amino-6-ethoxyquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-6-ethoxyquinoline-3-carboxylate (Example 13b) and ammonia as anoff white solid (77%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.31-1.40 (m, 6H),4.15 (q, J=7.2 Hz, 2H), 4.31 (q, J=6.8 Hz, 2H), 7.34 (q, J=6.4 Hz, 1H),7.69-7.74 (m, 2H), 8.21 (bs, 2H), 8.77 (s, 1H). MS 261 (MH⁺).

Example 13b ethyl 4-chloro-6-ethoxyquinoline-3-carboxylate

Prepared as in Example 1b from ethyl6-ethoxy-4-hydroxyquinoline-3-carboxylate (Example 13c) and POCl₃ aspale yellow solid (100%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.34-1.42 (m, 6H),4.21 (q, J=7.2 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 7.52 (d, J=2.8 Hz, 1H),7.56-7.59 (m, 1H), 8.02 (d, J=8.8 Hz, 1H), 8.94 (s, 1H). MS 280, 282(MH⁺).

Example 13c ethyl 6-ethoxy-4-hydroxyquinoline-3-carboxylate

Prepared as in Example 1c from 4-ethoxyaniline and diethyl2-(ethoxymethylene)malonate as a white solid (26%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.24-1.37 (m, 6H), 4.09 (q, J=6.8 Hz, 2H), 4.19 (q, J=7.2 Hz,2H), 7.29-7.32 (m, 1H), 7.52-7.56 (m, 2H), 8.47 (s, 1H), 12.27 (s, 1H).MS 262 (MH⁺).

Example 14 4-amino-6-propoxyquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-6-propoxyquinoline-3-carboxylate (Example 14a) as a white solid(56%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.01 (t, J=7.6 Hz, 3H), 1.77-1.82 (m,2H), 4.06 (t, J=6.8 Hz, 2H), 7.43 (d, J=2.0 Hz, 1H), 7.71-7.78 (m, 2H),8.77 (s, 1H). MS 247 (MH⁺).

Example 14a 4-amino-6-propoxyquinoline-3-carboxylate

Prepared as in Example 1a from ethyl4-chloro-6-propoxyquinoline-3-carboxylate (Example 14b) and ammonia as awhite solid. MS 275 (MH⁺).

Example 14b ethyl 4-chloro-6-propoxyquinoline-3-carboxylate

Prepared as in Example 1b from ethyl4-hydroxy-6-propoxyquinoline-3-carboxylate (Example 14c) and POCl₃ as apale yellow solid. MS 294, 296 (MH⁺).

Example 14c ethyl 4-hydroxy-6-propoxyquinoline-3-carboxylate

Prepared as in Example 1c from 4-propoxyaniline and diethyl2-(ethoxymethylene)malonate as a white solid (65%). ¹H NMR (400 MHz,DMSO-d₆) δ 0.98 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.72-1.77 (m,2H), 3.98 (t, J=6.0 Hz, 2H), 4.16-4.21 (m, 2H), 6.97-6.99 (m, 1H),7.53-7.56 (m, 2H), 8.47 (d, J=5.2 Hz, 1H), 12.27 (s, 1H). MS 276 (MH⁺).

Example 15 4-amino-5-methoxy-2-methylquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-5-methoxy-2-methylquinoline-3-carboxylate (Example 15a) as aoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.49 (s, 3H), 4.05 (s, 3H),7.19 (d, J=7.6 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H),9.49 (s, 1H), 9.85 (s, 1H). MS 233 (MH⁺).

Example 15a ethyl 4-amino-5-methoxy-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-methoxybenzonitrile and ethyl3-oxobutanoate as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.32(t, J=7.2 Hz, 3H), 2.55 (s, 3H), 3.96 (s, 3H), 4.30 (q, J=7.2 Hz, 2H),6.88 (d, J=8.4 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H),8.15 (s, 2H). MS 261 (MH⁺).

Example 16 4-amino-2-methyl-5-(neopentyloxy)quinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(neopentyloxy)quinoline-3-carboxylate (Example 16a)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.06 (s, 9H), 2.76 (s,3H), 3.93 (s, 2H), 7.05 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.66(t, J=8.0 Hz, 1H). MS 289 (MH⁺).

Example 16a ethyl4-amino-2-methyl-5-(neopentyloxy)quinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(neopentyloxy)benzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as a white solid (64%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.06(s, 9H), 1.32 (t, J=6.8 Hz, 3H), 2.54 (s, 3H), 3.86 (s, 2H), 4.31 (q,J=6.8 Hz, 2H). 6.88-6.91 (m, 1H), 7.22-7.25 (m, 1H), 7.50 (t, J=8.0 Hz,1H), 8.06 (s, 2H). MS 317 (MH⁺).

Example 17 4-amino-2-(carboxymethyl)quinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate (Example 17a) asa white solid (26%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.76 (s, 2H), 7.36 (t,J=8.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.64 (d, J=12.0 Hz, 1H), 7.87(bs, 2H), 8.17 (d, J=8.0 Hz, 1H). MS 188 (MH⁺—CH₂CO₂H).

Example 17a ethyl 4-amino-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate

Prepared as in Example 2a from 2-aminobenzonitrile and diethyl3-oxopentanedioate as a pale yellow solid (25%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.19 (t, J=8.0 Hz, 3H), 1.30 (t, J=8.0 Hz, 3H), 4.08 (m, 4H),4.28 (q, J=8.0 Hz, 2H), 7.50 (m, 1H), 7.73 (m, 2H), 8.10 (bs, 2H), 8.53(d, J=8.0 Hz, 1H). MS 303 (MH⁺).

Example 18 4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylicacid

To a solution of ethyl4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylate (Example18a, 16.8 g, 51.2 mmol) in EtOH (100 mL) was added NaOH (2 N, 64 mL) atroom temperature. The reaction mixture was refluxed for 4 h. After itwas cooled down to room temperature, the reaction solution was filteredto remove any possible solid residue. The filtrate was carefullyneutralized with 2N HCl to pH 7 at 0° C. The resultant precipitate wascollected by filtration, washed with water, re-dissolved in EtOH (500mL) and water (30 mL), and treated with activated charcoal (650 mg) at70° C. for 0.5 h. The charcoal was removed by filtration, and thefiltrate was concentrated and stored at 4° C. overnight. The resultingprecipitate was collected by filtration, washed with cold 25% EtOH inH₂O, and dried under vacuum at 60° C. overnight to give the titlecompound as an off-white solid (7.5 g, 49%). ¹H NMR (400 MHz, DMSO-d₆) δ1.31-1.37 (m, 2H), 1.53-1.64 (m, 4H), 1.79-1.85 (m, 2H), 2.47-2.50 (m,1H), 2.75 (s, 3H), 4.11 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.0 Hz, 1H), 7.26(d, J=8.4 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 8.77 (brs, 1H), 12.26 (brs,1H), 12.75 (brs, 1H). ¹H NMR (400 MHz, CD₃OD) δ 1.39-1.49 (m, 2H),1.63-1.77 (m, 4H), 1.91-1.98 (m, 2H), 2.51-2.61 (m, 1H), 2.78 (s, 3H),4.16 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H),7.72 (t, J=8.0 Hz, 1H). MS 301 (MH⁺).

Example 18a ethyl4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylate

To a solution of 2-amino-6-(cyclopentylmethoxy)benzonitrile (Tachdjian,C. et al. PCT Int. Appl. 2008, WO 2008154221) (21.63 g, 100.0 mmol) andethyl acetoacetate (12.6 mL, 100.0 mmol) in anhydrous toluene (300 mL)was added SnCl₄ (23.1 mL, 200.0 mmol) over a period of 25 minutes atroom temperature under nitrogen. The stirred reaction mixture was thenrefluxed for 5 h under nitrogen. After it was cooled down to roomtemperature, the reaction solution was concentrated to remove most ofthe solvent under reduced pressure. The residue was re-dissolved inEtOAc (3.5 L) and carefully neutralized to pH 8 with aqueous NaOHsolution (6.0 N, ˜130 mL) at 0° C. The resultant mixture was stirred atroom temperature overnight. The precipitate was filtered off, and theorganic layer was separated and washed with brine (400 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel eluting with 30% EtOAc in hexanesto give the title compound as a pale yellow solid (24.6 g, 75%). ¹H NMR(400 MHz, DMSO-d₆) δ 1.30-1.36 (m, 5H), 1.53-1.65 (m, 4H), 1.81-1.86 (m,2H), 2.42-2.45 (m, 1H), 2.54 (s, 3H), 4.05 (d, J=7.2 Hz, 2H), 4.31 (q,J=7.2 Hz, 2H), 6.89 (d, J=7.6 Hz, 1H), 7.21-7.23 (m, 1H), 7.50 (t, J=8.0Hz, 1H), 8.08 (s, 2H). MS 329 (MH⁺).

Example 19 4-amino-5-(cyclopentyloxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(cyclopentyloxy)-2-methylquinoline-3-carboxylate (Example 19a)as a off white solid (83%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.56-1.60 (m,2H), 1.67-1.70 (m, 2H), 1.83-1.87 (m, 2H), 1.92-1.96 (m, 2H), 2.67 (s,3H), 5.05-5.07 (m, 1H), 6.93 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H),7.57 (t, J=8.4 Hz, 1H). MS 287 (MH⁺).

Example 19a ethyl4-amino-5-(cyclopentyloxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(cyclopentyloxy)benzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as a yellow solid (40%). MS 315 (MH⁺).

Example 204-amino-2,3-butylene-6-methylthieno[2,3-b]pyridine-5-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-2,3-butylene-6-methylthieno[2,3-b]pyridine-5-carboxylate(Example 20a) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.78-1.79 (m, 4H),2.53 (s, 3H), 2.71-2.72 (m, 2H), 2.94-2.96 (m, 2H), 6.86 (s, 2H). MS 263(MH⁺).

Example 20a ethyl4-amino-2,3-butylene-6-methylthieno[2,3-b]pyridine-5-carboxylate

Prepared as in Example 2a from2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (Tachdjian,C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoateas a yellow solid. MS 291 (MH⁺).

Example 21 4-amino-5-(3,3-dimethylbutyl)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3,3-dimethylbutyl)-2-methylquinoline-3-carboxylate (Example21a) as a white solid (88%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.93 (s, 9H),1.40 (t, J=8.8 Hz, 2H), 2.75 (s, 3H), 3.17 (t, J=8.4 Hz, 2H), 7.35 (d,J=7.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 12.78 (s,1H). MS 287 (MH⁺).

Example 21a ethyl4-amino-5-(3,3-dimethylbutyl)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(3,3-dimethylbutyl)benzonitrile(Example 21b) and ethyl 3-oxobutanoate as a white solid (95%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.93 (s, 9H), 1.32 (t, J=7.2 Hz, 3H), 1.42-1.46 (m,1H), 2.55 (s, 3H), 3.11-3.15 (m, 2H), 4.33 (q, J=7.2 Hz, 2H), 7.12 (s,2H), 7.19-7.21 (m, 1H), 7.46-7.52 (m, 2H). MS 315 (MH⁺).

Example 21b 2-amino-6-(3,3-dimethylbutyl)benzonitrile

A suspension of 2-amino-6-(3,3-dimethylbut-1-ynyl)benzonitrile (Example21c, 690 mg, 3.48 mmol) and 10% Pd/C (100 mg) in EtOAc/EtOH (1:1, 20 mL)was stirred under an atmosphere of H₂ with a balloon at room temperatureovernight. The Pd/C was removed by filtration, the filtrate wasconcentrated, and purified by chromatography on silica gel eluting with20% EtOAc in hexanes to give the title compound as a light yellow oil(620 mg, 88%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.92 (s, 9H), 1.36-1.40 (m,2H), 2.52-2.56 (m, 2H), 5.88 (s, 2H), 6.45 (d, J=7.6 Hz, 1H), 6.57 (d,J=7.6 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H). MS 203 (MH⁺).

Example 21c 2-amino-6-(3,3-dimethylbut-1-ynyl)benzonitrile

To a solution of 2-amino-6-bromobenzonitrile (1.97 g, 10.0 mmol),3,3-dimethylbut-1-yne (2.46 g, 30 mmol), K₂CO₃ (2.76 g, 20.0 mmol), andCuI (191 mg, 0.1 mmol) in DME/H₂O (4:1, 50 mL) was added Pd(PPh₃)₄ (1.16g, 0.1 mmol) at room temperature under nitrogen. The reaction mixturewas refluxed under nitrogen overnight. After it was cooled down to roomtemperature, the reaction was quenched with brine, extracted with EtOAc.The organic layer was washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified by chromatography on silica geleluting with 20% EtOAc in hexanes to give the title compound as a lightbrown oil (1.84 g, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (s, 9H), 6.10(s, 2H), 6.59 (d, J=7.2 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 7.18-7.22 (m,1H). MS 199 (MH⁺).

Example 22 4-amino-5-(2-ethylbutoxy)-2-methylquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-5-(2-ethylbutoxy)-2-methylquinoline-3-carboxylate (Example 22a)as a white solid (45%). M.p.: 145-151° C. ¹H NMR (400 MHz, DMSO-d₆) δ0.90 (t, J=8 Hz, 6H), 1.48-1.41, (m, 4H), 1.84-1.78 (m, 1H), 2.73 (s,3H), 4.11 (d, J=8 Hz, 2H), 6.99 (d, J=8 Hz, 1H), 7.32 (d, J=8 Hz, 1H),7.59 (t, J=8 Hz, 1H), 8.40 (brs, 1H), 11.09 (brs, 1H), 13.91 (brs, 1H).MS 303 (MH⁺).

Example 22a ethyl4-amino-5-(2-ethylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(2-ethylbutoxy)benzonitrile(Example 22b) and ethyl 3-oxobutanoate as a white solid (89%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.90 (t, J=8 Hz, 6H), 1.32 (t, J=8 Hz, 3H),1.48-1.41 (m, 4H), 1.79-1.73 (m, 1H), 2.54 (s, 3H), 4.08 (d, J=4 Hz,2H), 4.31 (q, J=8 Hz, 2H), 6.92 (dd, J=2, 8 Hz, 1H), 7.23 (dd, J=2, 8Hz, 1H), 7.50 (t, J=8 Hz, 1H), 8.04 (brs, 1H). MS 331 (MH⁺).

Example 22b 2-amino-6-(2-ethylbutoxy)benzonitrile

To a solution of 2-ethylbutan-1-ol (1.02 g, 10.0 mmol) in dry THF (60mL) was carefully added NaH (60% in mineral oil, 480 mg, 12.0 mmol) insmall portions at 0° C. under nitrogen. The reaction mixture was stirredat 0° C. under nitrogen for 2 hrs. To this solution was added2-amino-6-fluorobenzonitrile (1.36 g, 10.0 mmol), and the reactionsolution was stirred at 0° C.-RT for 2 hrs, and then at 65° C. overnightunder nitrogen. The reaction was cooled down to room temperature thenquenched with brine, and extracted with EtOAc (3×). The combined organiclayers were washed with brine, dried over Na₂SO₄. Filtered andevaporated under reduced pressure. The residue was purified bychromatography on silica gel (eluent: 20% EtOAc in hexanes) to give thetitle compound as colorless oil (1.29 g, 59%). ¹H NMR (400 MHz, CDCl₃) δ0.93 (t, J=8 Hz, 6H), 1.55-1.43 (m, 4H), 1.73-1.65 (m, 1H), 3.90 (d, J=4Hz, 2H), 4.10 (brs, 2H), 6.25 (d, J=8 Hz, 1H), 6.34 (d, J=8 Hz, 1H),7.20 (t, J=8 Hz, 1H).

Example 23 4-amino-5-(heptan-4-yloxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(heptan-4-yloxy)-2-methylquinoline-3-carboxylate (Example 23a)as a white solid (59%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.87 (t, J=7.2 Hz,6H), 1.49-1.25 (m, 4H), 1.84-1.60 (m 4H), 2.74 (s, 3H), 4.74-4.71 (m,1H), 7.07 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.4 Hz,1H), 8.82 (brs, 1H). MS 317 (MH⁺).

Example 23a ethyl4-amino-5-(heptan-4-yloxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(heptan-4-yloxy)benzonitrile(Example 23b) and ethyl 3-oxobutanoate as a pale yellow solid (65%). ¹HNMR (400 MHz, DMSO-d₆) δ 0.87 (t, J=7.2 Hz, 6H), 1.31 (t, J=7.2 Hz, 3H),1.47-1.33 (m, 4H), 1.77-1.59 (m, 4H), 2.54 (s, 3H), 4.30 (q, J=7.2 Hz,2H), 4.67-4.64 (m, 1H), 6.92 (d, J=7.6 Hz, 1H), 7.19 (dd, J=0.8, 8.4 Hz,1H), 7.49 (t, J=8.0 Hz, 1H), 8.13 (brs, 2H). MS 345 (MH⁺).

Example 23b 2-amino-6-(heptan-4-yloxy)benzonitrile

Prepared as in Example 22b from heptan-4-ol and2-amino-6-fluorobenzonitrile as a white solid (24%). ¹H NMR (400 MHz,CDCl₃) δ 0.92 (t, J=7.2 Hz, 6H), 1.55-1.31 (m, 8H), 3.88 (s, br, 1H),4.33-4.27 (m, 1H), 6.26 (d, J=8.0 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 7.20(t, J=8.0 Hz, 1H).

Example 244-amino-5-(2-(isonicotinamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(isonicotinamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24a) as a white solid (67%). M.p.: 195-198° C. ¹H NMR (400 MHz,DMSO-d₆) δ 1.51 (s, 6H), 2.75 (s, 3H), 4.48 (s, 2H), 7.07 (d, J=8 Hz,1H), 7.31 (d, J=8 Hz, 1H), 7.67 (t, J=8 Hz, 1H), 7.70 (dd, J=1, 8 Hz,2H), 8.50 (s, 1H), 8.67 (dd, J=1, 8 Hz, 2H), 8.76 (brs, 1H), 12.19 (brs,1H), 12.85 (brs, 1H). MS 395 (MH⁺).

Example 24a ethyl4-amino-5-(2-(isonicotinamido)-2-methylpropoxy)-2-methylquino-line-3-carboxylate

To a solution of ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b, 1.0 g, 3.15 mmol) in dry DMF (20 mL) was addedisonicotinic acid (504 mg, 4.10 mmol), followed by EDCI (783 mg, 4.10mmol), HOBt (554 mg, 4.10 mmol), and triethylamine (414 mg, 4.10 mmol)at room temperature under nitrogen. After it was stirred at roomtemperature for 12 hrs, the reaction mixture was concentrated underreduced pressure. The residue was diluted with water, and extracted withEtOAc (3×). The aqueous layer was basified with 2N NaOH to pH 8 andextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried over MgSO₄, filtered, concentrated, and purified bychromatography on silica gel eluting with 10% MeOH in dichloromethane togive the title compound as a yellow solid (1.1 g, 83%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.29 (t, J=4 Hz, 3H), 1.51 (s, 6H), 2.94 (s, 3H), 4.28 (q,J=4 Hz, 2H), 4.42 (s, 2H), 6.93 (dd, J=1, 8 Hz, 1H), 7.24 (dd, J=1, 8Hz, 2H), 7.52 (t, J=8 Hz, 1H), 7.69 (dd, J=2, 4 Hz, 2H), 8.14 (s, 2H),8.37 (s, 1H), 8.67 (dd, J=2, 4 Hz, 2H). MS 423 (MH⁺).

Example 24b ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from benzyl1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-ylcarbamate (Example 24c)and ethyl 3-oxobutanoate as a yellow-brown solid (91%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.15 (s, 6H), 1.31 (t, J=4 Hz, 3H), 2.54 (s, 3H), 3.87 (s,2H), 4.31 (q, J=4 Hz, 2H), 6.85 (d, J=4 Hz, 1H), 7.21 (d, J=4 Hz, 1H),7.49 (t, J=8 Hz, 1H), 8.38 (brs, 2H). MS 318 (MH⁺).

Example 24c benzyl1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-ylcarbamate

To a solution of 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile(Example 24d, 30.5 g, 148.6 mmol) in THF/H₂O (1:1, 400 mL) was addedNaHCO₃ (24.7 g, 294 mmol), followed by benzyl (2,5-dioxopyrrolidin-1-yl)carbonate (44.0 g, 176 mmol) at room temperature. The reaction wasstirred at room temperature for 4 h then the organic layer was separatedand the aqueous layer was extracted with EtOAc (2×). The combinedorganic layers were washed with brine and dried over MgSO₄. Afterfiltration, the solvent was evaporated and the crude oil was purified bychromatography on silica gel (eluent: 0-60% EtOAc in hexane) to give thetitle compound as yellow oil (44.8 g, 89%). ¹H NMR (400 MHz, DMSO-d₆) δ1.30 (s, 6H), 4.02 (s, 2H), 4.96 (s, 2H), 5.98 (s, 2H), 6.14 (d, J=8.0Hz, 1H), 6.32 (dd, J=0.8, 8.4 Hz, 1H), 7.12 (t, J=8.4 Hz, 1H), 7.38-7.21(m, 6H). MS 340 (MH⁺).

Example 24d 2-amino-6-(2-amino-2-methylpropoxy)benzonitrile

To a solution of 2-amino-2-methylpropan-1-ol (14.4 g, 161 mmol) inanhydrous THF (150 mL) was added NaH (6.8 g, 161 mmol, 60% in mineraloil) in small portions at 0° C. under nitrogen. The mixture was stirredat 0° C. for 30 minutes and then stirred at room temperature for another30 minutes. The solution was cooled down to 0° C. again, and to thissolution was added dropwise a solution of 2-amino-6-fluorobenzonitrile(20.0 g, 147 mmol) in anhydrous THF (50 mL). The reaction mixture wasthen refluxed overnight under nitrogen. The reaction mixture was cooleddown to room temperature and carefully quenched with aqueous NH₄Clsolution and extracted with ethyl acetate (3×). The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated. The crude mixture was purified by chromatography on silicagel eluting with 10% MeOH in DCM to give the title compound as yellowsolid (23.4 g 71%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.08 (s, 6H), 3.15 (s,2H), 3.64 (s, 2H), 5.98 (s, 2H), 6.13 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4Hz, 1H), 7.15 (t, J=8.4 Hz, 1H). MS 236 (MH⁺).

Example 254-amino-5-(2-(3-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-hydroxybenzamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate(Example 25a) as a white solid (65%). M.p.: 195-198° C. ¹H NMR (400 MHz,DMSO-d₆) δ 1.48 (s, 6H), 2.75 (s, 3H), 4.47 (s, 2H), 6.87 (dt, J=8, 4Hz, 1H), 7.22-7.16 (m, 3H), 7.06 (d, J=8 Hz, 1H), 7.27 (d, J=8 Hz, 1H),7.67 (t, J=8 Hz, 1H), 8.08 (s, 1H), 8.84 (brs, 1H), 9.69 (s, 1H), 12.12(brs, 1H), 12.78 (brs, 1H). MS 410 (MH⁺).

Example 25a ethyl4-amino-5-(2-(3-hydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate(Example 24b) and 3-hydroxybenzoic acid as a yellow-brown solid (64%).¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (t, J=4 Hz, 3H), 1.48 (s, 6H), 2.55 (s,3H), 4.30 (q, J=4 Hz, 2H), 4.41 (s, 2H), 6.85-6.88 (m, 1H), 6.92 (d, J=8Hz, 1H), 7.25-7.15 (m, 4H), 7.52 (t, J=8 Hz, 1H), 7.98 (s, 1H), 8.19 (s,2H), 9.59 (s, 1H). MS 438 (MH⁺).

Example 26(S)-4-amino-5-(2-(cyclohexanecarboxamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(cyclohexanecarboxamido)-propoxy)-2-methylquinoline-3-carboxylate(Example 26a) as a white solid (53%). ¹H NMR (400 MHz, DMSO-d₆) δ1.25-1.10 (m, 5H), 1.34-1.31 (m, 2H), 1.69-1.62 (m, 5H), 2.11-2.05 (m,1H), 2.69 (s, 3H), 3.93 (t, J=9.2 Hz, 1H), 4.13 (dd, J=4, 9.6 Hz, 1H),4.14-4.11 (m, 1H), 6.86 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.49(t, J=8.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H). MS 386 (MH⁺).

Example 26a (S)-ethyl4-amino-5-(2-(cyclohexanecarboxamido)propoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and cyclohexanecarboxylic acid as brown solid (28%). MS 414 (MH⁺).

Example 26b (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from (S)-benzyl(1-(3-amino-2-cyanophenoxy)propan-2-yl)-carbamate (Example 26c) andethyl 3-oxobutanoate as brown solid. MS 304 (MH⁺).

Example 26c (S)-benzyl (1-(3-amino-2-cyanophenoxy)propan-2-yl)carbamate

Prepared as in Example 24c from(S)-2-amino-6-(2-aminopropoxy)benzonitrile (Example 26d) as brown solid(86%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (d, J=6.4 Hz, 3H), 3.81 (d,J=8.4 Hz, 1H), 3.95-3.92 (m, 1H), 4.99 (s, 2H), 5.36 (s, 2H), 5.96 (s,2H), 6.20 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.13 (t, J=8.4 Hz,1H), 7.44-7.38 (m, 5H). MS 326 (MH⁺).

Example 26d (S)-2-amino-6-(2-aminopropoxy)benzonitrile

Prepared as in Example 24d from (S)-2-aminopropan-1-ol and2-amino-6-fluoro-benzonitrile as brown solid (73%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.01 (d, J=6.5 Hz, 3H), 3.08 (m, 1H), 3.71 (d, J=6.1 Hz, 2H),5.95 (s, 2H), 6.15 (d, J=8.3 Hz, 1H), 6.2 (d, J=8.3 Hz, 1H), 7.13 (t,J=8.3 Hz, 1H). MS 192 (MH⁺).

Example 27(S)-4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylate(Example 27a) as an off-white solid (42%). ¹H NMR (400 MHz, DMSO-d₆) δ1.31 (d, J=6.8 Hz, 3H), 2.66 (s, 3H), 4.14 (t, J=9.2 Hz, 1H), 4.28 (dd,J=3.6, 9.6 Hz, 1H), 4.70-4.55 (m, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.26 (d,J=8.4 Hz, 1H), 7.51 (t, J=8.4 Hz, 1H), 7.75 (dd, J=1.2, 6.0 Hz, 2H),8.71 (dd, J=1.2, 6.0 Hz, 2H), 8.95 (d, J=8.0 Hz, 1H). MS 409 (MH⁺).

Example 27a (S)-ethyl4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and isonicotinic acid as brown solid (36%). MS 409 (MH⁺).

Example 28(S)-4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 28a) as a white solid (58%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.28(d, J=7.2 Hz, 3H), 2.65 (s, 3H), 4.11 (t, J=8.8 Hz, 1H), 4.22 (dd,J=4.0, 10 Hz, 1H), 4.65-4.55 (m, 1H), 6.88 (d, J=8.0, 2H), 7.25-7.13 (m,4H), 7.48 (t, J=8.0 Hz, 1H), 8.49 (d, J=8.0, 1H), 9.93 (brs, 1H). MS 396(MH⁺).

Example 28a (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 3-hydroxybenzoic acid as brown solid (41%). MS 424 (MH⁺).

Example 294-amino-5-(3-(cyclopentylamino)-2,2-dimethyl-3-oxopropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cyclopentylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 29a) as a white powder (74%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.27(s, 6H), 1.36-1.46 (m, 4H), 1.57-1.59 (m, 2H), 1.72-1.78 (m, 2H), 2.78(s, 3H), 4.04 (m, 1H), 4.19 (s, 2H), 7.02 (d, J=8.0 Hz, 1H), 7.33 (d,J=8.0 Hz, 1H), 7.64-7.71 (m, 2H), 8.83 (brs, 1H), 12.25 (brs, 1H), 12.93(brs, 1H). MS 386 (MH⁺).

Example 29a ethyl4-amino-5-(3-(cyclopentylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)-N-cyclopentyl-2,2-dimethylpropanamide(Example 29b) and ethyl 3-oxobutanoate as a bright yellow solid (62%).¹H NMR (400 MHz, DMSO-d₆) δ 1.26 (s, 6H), 1.34 (t, J=8.0 Hz, 3H),1.40-1.46 (m, 4H), 1.57-1.59 (m, 2H), 1.74-1.77 (m, 2H), 2.57 (s, 3H),4.09 (q, J=4.0 Hz, 1H), 4.15 (s, 2H), 4.33 (q, J=8.0 Hz, 2H), 6.89 (d,J=4.0 Hz, 1H), 7.26 (dd, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.56 (s,1H), 8.09 (brs, 2H). MS 414 (MH⁺).

Example 29b3-(3-amino-2-cyanophenoxy)-N-cyclopentyl-2,2-dimethylpropanamide

Prepared as in Example 22b fromN-cyclopentyl-3-hydroxy-2,2-dimethylpropanamide (Example 29c) and2-amino-6-fluorobenzonitrile as a white solid (45%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.19 (s, 6H), 1.40-1.49 (m, 4H), 1.61-1.63 (m, 2H), 1.74-1.79(m, 2H), 3.95 (s, 2H), 4.03 (m, 1H), 5.98 (s, 2H), 6.19 (d, J=8.0 Hz,1H), 6.33 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz,1H). MS 302 (MH⁺).

Example 29c N-cyclopentyl-3-hydroxy-2,2-dimethylpropanamide

Prepared as in Example 24a from hydroxypivalic acid and cyclopentylamine as an orange oil (32%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.00 (s, 6H),1.32-1.40 (m, 2H), 1.43-1.49 (m, 2H), 1.57-1.65 (m, 2H), 1.73-1.81 (m,2H), 3.34 (d, J=4.0 Hz, 2H), 3.98 (m, 1H), 4.87 (t, J=4.0 Hz, 1H), 7.22(d, J=4.0 Hz, 1H). MS 186 (MH⁺).

Example 30 4-Amino-5-(cyclobutylmethoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(cyclobutylmethoxy)-2-methylquinoline-3-carboxylate (Example30a) as a white powder (51%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.84-1.99 (m,4H), 2.10-2.15 (m, 2H), 2.77 (s, 3H), 2.92 (m, 1H), 4.23 (d, J=8.0 Hz,2H), 7.05 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.68 (t, J=8.0 Hz,1H), 8.71 (brs, 1H), 12.23 (brs, 1H), 12.81 (brs, 1H). MS 287 (MH⁺).

Example 30a ethyl4-amino-5-(cyclobutylmethoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(cyclobutylmethoxy)benzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as an orange solid (26%). ¹H NMR (400 MHz, DMSO-d₆) δ1.32 (t, J=8.0 Hz, 3H), 1.83-1.90 (m, 4H), 2.10-2.13 (m, 2H), 2.59 (s,3H), 2.86 (m, 1H), 4.16 (d, J=4.0 Hz, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.90(d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.05(brs, 2H). MS 315 (MH⁺).

Example 314-amino-5-(2-(cyclopentanecarboxamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(cyclopentanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 31a) as an off-white solid (68%). ¹H NMR (400 MHz, DMSO-d₆) δ1.36 (s, 6H), 1.43-1.51 (m, 6H), 1.65-1.69 (m, 2H), 2.58 (m, 1H), 2.78(m, 3H), 4.37 (s, 2H), 7.04 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.68 (m,1H), 7.80 (s, 1H), 8.84 (brs, 1H), 12.42 (brs, 1H), 12.73 (brs, 1H). MS386 (MH⁺).

Example 31a ethyl4-amino-5-(2-(cyclopentanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-5-(2-amino-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate(Example 24b) and cyclopentane carboxylic acid as a yellow solid (33%).¹H NMR (400 MHz, DMSO-d₆) δ 1.34 (t, J=4.0 Hz, 3H), 1.37 (s, 6H),1.42-1.53 (m, 6H), 1.64-1.69 (m, 2H), 2.58 (m, 1H), 2.62 (s, 3H), 4.32(s, 2H), 4.35 (m, 2H), 6.96 (m, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.58 (m,1H), 7.66 (s, 1H), 8.41 (d, 2H). MS 414 (MH⁺).

Example 32 4-Amino-5-(cycloheptyloxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(cycloheptyloxy)-2-methylquinoline-3-carboxylate (Example 32a)as a light yellow solid (34%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.49-1.65 (m,8H), 1.83-1.89 (m, 2H), 2.04-2.09 (m, 2H), 2.74 (s, 3H), 4.85 (m, 1H),7.03 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H),8.82 (brs, 1H), 12.24 (brs, 1H), 12.64 (brs, 1H). MS 315 (MH⁺).

Example 32a ethyl4-amino-5-(cycloheptyloxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(cycloheptyloxy)benzonitrile(Example 32b) and ethyl 3-oxobutanoate as a bright yellow solid (72%).¹H NMR (400 MHz, DMSO-d₆) δ 1.32 (t, J=8.0 Hz, 3H), 1.49-1.65 (m, 8H),1.78-1.87 (m, 2H), 2.04-2.10 (m, 2H), 2.53 (s, 3H). 4.31 (q, J=8.0 Hz,2H), 4.79 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.49(t, J=8.0 Hz, 1H), 8.14 (brs, 2H). MS 343 (MH⁺).

Example 32b 2-amino-6-(cycloheptyloxy)benzonitrile

Prepared as in Example 22b from cycloheptanol and2-amino-6-fluorobenzonitrile as yellow oil (11%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.42-1.71 (m, 10H), 1.88-1.93 (m, 2H), 4.56 (m, 1H), 5.95 (s,2H), 6.20 (d, J=8.0 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz,1H). MS 231 (MH⁺).

Example 33 4-Amino-2-methyl-5-(3-phenoxypropoxy)quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(3-phenoxypropoxy)quinoline-3-carboxylate (Example33a) as a yellow solid (90%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.35 (m, 2H),2.77 (s, 3H), 4.19 (t, J=4.0 Hz, 2H), 4.42 (t, J=4.0 Hz, 2H), 6.91-6.96(m, 3H), 7.09 (d, J=8.0 Hz, 1H), 7.26-7.30 (m, 3H), 7.70 (t, J=8.0 Hz,1H), 8.96 (brs, 1H), 12.24 (brs, 1H), 12.75 (brs, 1H). MS 353 (MH⁺).

Example 33a ethyl4-amino-2-methyl-5-(3-phenoxypropoxy)quinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(3-phenoxypropoxy)benzonitrile(Example 33b) and ethyl 3-oxobutanoate as a yellow solid (47%). ¹H NMR(400 MHz, DMSO-d₆) δ 1.33 (t, J=8.0 Hz, 3H), 2.34 (m, 2H), 2.57 (s, 3H),4.19 (t, J=4.0 Hz, 2H), 4.33 (q, J=8.0 Hz, 2H), 4.37 (t, J=4.0 Hz, 2H),6.91-6.97 (m, 4H), 7.24-7.29 (m, 3H), 7.53 (t, J=8.0 Hz, 1H), 8.17 (s,2H). MS 381 (MH⁺).

Example 33b 2-amino-6-(3-phenoxypropoxy)benzonitrile

Prepared as in Example 22b from 3-phenoxy-1-propanol and2-amino-6-fluorobenzo-nitrile as a yellow oil (93%). ¹H NMR (400 MHz,DMSO-d₆) δ 2.14 (m, 2H), 4.10-4.16 (m, 4H), 5.98 (s, 2H), 6.23 (d, J=8.0Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 6.89-6.94 (m, 5H), 7.16 (t, J=8.0 Hz,1H).

Example 3444-Amino-5-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 34a) as an orange powder (23%). ¹H NMR (400 MHz, DMSO-d₆) δ1.24 (brs, 2H), 1.79-1.88 (m, 2H), 2.29 (m, 1H), 2.77 (s, 3H), 3.07(brs, 2H), 3.65 (brs, 1H), 4.17 (d, J=8.0 Hz, 2H), 4.50 (brs, 1H),6.74-6.83 (m, 3H), 7.07 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.29(d, J=8.0 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 8.74 (brs, 1H), 9.75 (s, 1H),12.25 (brs, 1H), 12.71 (brs, 1H). MS 436 (MH⁺).

Example 34a ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)benzonitrile(Example 34b) and ethyl 3-oxobutanoate as a yellow solid (49%). ¹H NMR(400 MHz, DMSO-d₆) δ 1.24 (m, 2H), 1.31 (t, J=4.0 Hz, 3H), 1.77-1.89 (m,2H), 2.22 (brs, 1H), 2.55 (s, 3H), 2.79 (brs, 1H), 3.04 (brs, 1H), 3.64(brs, 1H), 4.10 (m, 2H), 4.32 (q, J=8.0 Hz, 2H), 4.49 (brs, 1H),6.71-6.82 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 7.19-7.25 (m, 2H), 7.52 (t,J=8.0 Hz, 1H), 8.06 (brs, 2H), 9.64 (s, 1H). MS 464 (MH⁺).

Example 34b2-amino-6-((1-(3-hydroxybenzoyl)piperidin-4-yl)methoxy)benzonitrile

Prepared as in Example 24a from2-amino-6-(piperidin-4-ylmethoxy)benzonitrile (Example 34c) and3-hydroxybenzoic acid as an orange glass (66%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.29 (m, 2H), 1.66-1.92 (m, 2H), 2.06 (m, 1H), 2.80 (brs,1H), 3.05 (brs, 1H), 3.62 (brs, 1H), 3.91 (d, J=8.0 Hz, 2H), 4.49 (brs,1H), 5.99 (s, 2H), 6.22 (d, J=8.0 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H),6.72-6.83 (m, 3H), 7.15-7.24 (m, 2H), 9.65 (s, 1H). MS 352 (MH⁺).

Example 34c 2-amino-6-(piperidin-4-ylmethoxy)benzonitrile

To a solution of tert-butyl4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 34d,1.33 g, 4.0 mmol) in EtOAc (20 mL) was added dropwise aqueous HClsolution (12 N, 6.6 mL) at 0° C. The reaction mixture was stirred atroom temperature overnight. The solvent was removed under reducedpressure to give the title compound (100%) as a brown solid, which ispure enough and used directly in the next step without furtherpurification. MS 232 (MH⁺).

Example 34d 2 tert-butyl4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 22b from N-Boc-4-piperidinemethanol and2-amino-6-fluoro-benzonitrile as an off-white solid (37%). ¹H NMR (400MHz, DMSO-d₆) δ 1.15-1.21 (m, 2H), 1.40 (s, 9H), 1.74 (m, 2H), 1.99(brs, 1H), 2.74 (brs, 2H), 3.87 (d, J=4.0 Hz, 2H), 3.96 (m, 2H), 5.99(s, 2H), 6.21 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0Hz, 1H). MS 232 (MH⁺—Boc).

Example 354-Amino-5-((1-butyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 ethyl4-amino-5-((1-butyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 35a) as a white solid (61%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.87(t, J=8.0 Hz, 3H), 1.05-1.22 (m, 2H), 1.50 (m, 2H), 1.80 (m, 2H),2.24-2.31 (m, 3H), 2.65 (s, 3H), 3.02 (2H), 3.88-3.92 (m, 1H), 4.11 (m,2H), 4.44 (m, 1H), 7.05 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.69 (m, 1H),8.76 (brs, 1H), 12.33 (brs, 1H), 12.65 (brs, 1H). MS 386 (MH⁺).

Example 35a ethyl4-amino-5-((1-butyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-2-methyl-5-(piperidin-4-ylmethoxy)-quinoline-3-carboxylate(Example 35b) and butyric acid as a yellow oil (50%). MS 414 (MH⁺).

Example 35b ethyl4-amino-2-methyl-5-(piperidin-4-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from benzyl4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 35c)and ethyl 3-oxobutanoate as an orange solid (25%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.29-1.37 (m, 5H), 1.77-1.80 (m, 2H), 2.07 (brs, 1H), 2.53(s, 3H), 2.55-2.65 (m, 3H), 3.06-3.09 (m, 2H), 4.06 (d, J=8.0 Hz, 2H),4.32 (q, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H),7.51 (t, J=8.0 Hz, 1H), 8.08 (s, 2H). MS 344 (MH⁺).

Example 35c 4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 22b from 1-N-Cbz-4-(hydroxymethyl)piperidine and2-amino-6-fluoro-benzonitrile as a yellow oil (18%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.20-1.25 (m, 2H), 1.75-1.78 (m, 2H), 1.96 (brs, 1H), 3.88(d, J=8.0 Hz, 2H), 3.99-4.04 (m, 4H), 5.07 (s, 2H), 5.99 (s, 2H), 6.21(d, J=8.0 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H),7.29-7.40 (m, 5H). MS 366 (MH⁺).

Example 36 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acid

To a solution of ethyl4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (Example 36a,110 g, 0.335 mol) in EtOH (450 mL) was added a solution of NaOH (33.5 g,0.837 mol) in water (200 mL) at room temperature. The reaction mixturewas then refluxed overnight. The reaction solution was cooled down to 0°C. and carefully neutralized with 4N HCl to pH 7. The resultant solutionwas concentrated under reduced pressure to remove most of the EtOH. Theprecipitate was collected by filtration, and re-dissolved in EtOH (4 L)at 65° C. and treated with activated charcoal (5 g) for 0.5 h. Thecharcoal was removed by filtration over celite, and the filtrate wasconcentrated. The precipitate was collected by filtration, washed withcold water, and dried under vacuum at 60° C. overnight to give the titlecompound as a white solid (100 g, 99%). M.p.: 220.0-221.5° C. ¹H NMR(400 MHz, DMSO-d₆) δ 1.28-1.72 (m, 8H), 2.00-2.04 (m, 2H), 2.75 (s, 3H),4.69-4.71 (m, 1H), 7.10-7.12 (d, J=8.0 Hz, 1H), 7.24-7.26 (d, J=8.0 Hz,1H), 7.65 (t, J=8.0 Hz, 1H), 12.80 (brs, 1H). MS 301 (MH⁺). ElementalAnalysis Calculated (Found) for C₁₇H₂₀N₂O₃: C, 67.98% (67.74%); H, 6.71%(7.01%); N, 9.33% (9.40%).

Example 36a ethyl4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate

A solution of ethyl 3-oxobutanoate (29.9 g, 0.230 mol) in anhydroustoluene (200 mL) was added to a solution of2-amino-6-(cyclohexyloxy)benzonitrile (Example 36b, 49.8 g, 0.230 mol)in anhydrous toluene (1000 mL) under nitrogen in a 3 L round bottomflask sitting in an oil bath at room temperature. SnCl₄ (53.9 mL, 0.461mol) was added slowly over a period of approximately 1 h. The oil bathtemperature was then raised to 110° C. and the reaction mixture wasstirred at that temperature for 2.5 h. It was then cooled down to 5° C.,still under nitrogen, and the toluene was decanted away from theimmiscible viscous oil at the bottom of the flask. The viscous oil wasfurther concentrated under vacuum at 60° C., re-dissolved in boilingethyl acetate (1 L), and transferred to a 4 liter Erlenmeyer flask. Thesolution was diluted with more EtOAc (1.5 L), cooled down to −15° C.,and neutralized with NaOH (3 N, 500 mL). The organic layer wasseparated, and the aqueous emulsion was extracted once more with ethylacetate. The insoluble tin salts were filtered out from the aqueouslayer, then both the salts and aqueous filtrate were washed once morewith ethyl acetate. The combined organic layers were dried over MgSO₄,concentrated, and passed through a silica column using 0% to 60% ethylacetate in hexanes. The product was purified by recrystallization fromEtOAc to give the title compound as an off-white solid (64.3 g, 85%). ¹HNMR (400 MHz, DMSO-d₆) δ 1.28-1.34 (m, 1H), 1.32 (t, 3H), 1.37-1.45 (m,2H), 1.51-1.63 (m, 3H), 1.67-1.71 (m, 2H), 1.99-2.03 (m, 2H), 2.54 (s,3H), 4.28-4.33 (q, J=6.8 Hz, 2H), 4.64 (m, 1H), 6.95-6.97 (d, J=7.6 Hz,1H), 7.19-7.21 (d, J=8.4 Hz, 1H), 7.65 (t, J=8.4 Hz, 1H), 8.15 (brs,2H). MS 329 (MH⁺).

Example 36b 2-amino-6-(cyclohexyloxy)benzonitrile

To a solution of cyclohexanol (19.1 g, 0.191 mol) in anhydrous THF (500mL) was added NaH (7.6 g, 40% in mineral oil, 0.191 mol) in smallportions at 0° C. under nitrogen. The mixture was stirred at roomtemperature for 1 h and a solution of 2-amino-6-fluorobenzonitrile (20.0g, 0.15 mol) in anhydrous THF (150 mL) was added drop-wise at roomtemperature. The reaction mixture was heated to reflux overnight thencooled to room temperature and most of the THF removed under reducedpressure. Ice water (100 mL) was added to the concentrated reactionmixture followed by EtOAc (500 mL). The organic layer was separated andsuccessively washed with water and brine, dried over Na₂SO₄, filteredand evaporated under reduced pressure. The residue was purified bychromatography on silica gel eluting with 25-30% EtOAc in hexanes togive 2-amino-6-(cyclohexyloxy)benzonitrile as a light yellow oil (17.9g, 56%). ¹H NMR (400 MHz, CDCl₃) δ 1.32-1.43 (m, 3H), 1.51-1.55 (m, 1H),1.62-1.69 (m, 2H), 1.79-1.95 (m, 4H), 4.31-4.36 (m, 3H), 6.23-6.27 (m,2H), 7.18 (d, J=8.0 Hz, 1H). MS 329 (MH⁺).

Example 36b 2-amino-6-(cyclohexyloxy)benzonitrile

Alternative Methode a):

To a solution of 2-(cyclohexyloxy)-6-nitrobenzonitrile (Example 36c,50.0 g, 0.20 mol) in THF/AcOH (1:1 by volume, 500 mL) was added ironpowder (34.0 g, 0.61 mol) in one portion at room temperature undernitrogen. The reaction mixture was refluxed for 40 min under nitrogenand cooled down to room temperature and EtOAc (2 L) was added. Theprecipitate that formed was filtered off and washed with EtOAc. Theorganic layer was separated and washed successively with water (2×300mL), aqueous NaOH (1.0 N, 2×300 mL), saturated Na₂CO₃ solution (300 mL),brine (300 mL), dried over Na₂SO₄ filtered and evaporated under reducedpressure. The residue was purified by chromatography on silica geleluting with 25% EtOAc in hexanes to give2-amino-6-(cyclohexyloxy)benzonitrile as a pale yellow oil (45.0 g,94%), which solidified after storage overnight at room temperature.

Alternative Methode b):

A 3-L 3-neck round bottom flask was first purged with nitrogen. 10% Pd/C(2.81 g) was then added under nitrogen, followed successively by2-(cyclohexyloxy)-6-nitrobenzonitrile (Example 36c, 43.2 g, 0.175 mol),anhydrous methanol (389 mL), and acetic acid (80.4 mL). A refluxcondenser, a dropping funnel containing a solution of ammonium formate(49.8 g, 0.790 mol) in anhydrous methanol (498 mL), thermometer,nitrogen inlet and nitrogen outlet were attached. Ammonium formatesolution (75 mL) was added at room temperature, then the reaction wasslowly heated to a maximum of 42° C. The mixture was monitored carefullyuntil initiation of the reaction was observed (an evolution of gasoccurred with roughly a 10° C. exotherm). Initiation of the reactionoften took up to 40 minutes before starting. The remaining of theammonium formate solution was then added at a rate which maintained aninternal reaction temperature of 40° C. to 48° C. After the addition wascomplete, the reaction mixture was stirred for another 10 minutes at 45°C., then cooled down to room temperature. The Pd/C was filtered outusing a Teflon filter, and the solvent was evaporated. Ice water (1 L)was added to the residue, then the water was decanted and discarded. Theresidue was dissolved in diethyl ether, washed with water, thensaturated sodium bicarbonate solution, then dried with magnesium sulfateand concentrated. The product was then purified on silica gel usingisocratic DCM to give the product as a yellow oil (31.5 g, 83%).

Example 36c 2-(cyclohexyloxy)-6-nitrobenzonitrile

To a solution of cyclohexanol (46.8 grams, 0.467 mol) in anhydrous THF(1 L) was added sodium hydride (20.3 grams, 0.508 mol) at −40° C. undernitrogen. The reaction mixture was allowed to warm slowly to roomtemperature and stir for another 1 hour. It was then cooled down to −55°C. and 2,6-dinitrobenzonitrile (78.4 g, 0.406 mol) was added. Thereaction was stirred at room temperature overnight, then cooled down to−20° C., and citric acid (23.4 grams, 0.122 mol) was added. The mixturewas then poured into ice water (5 L) which contained citric acid (7.8 g,0.041 mol), stirred for 15 minutes, and the precipitated product wascollected by filtration. The crude product was recrystallized fromisopropanol (750 mL, heated to boiling, then cooled down to 0° C.),filtered, washed with isopropanol (300 mL), then air dried to give 84.4g yellow solid. The solid was dissolved in dichloromethane (169 mL) andfiltered through a plug of alumina to give the title compound as a paleyellow solid (83.2 g, 83.2%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.4 (m, 4H),1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 2H), 4.75 (m, 1H), 7.79 (dd, J=2.0,8.0 Hz, 1H), 7.84-7.91 (m, 2H).

Example 374-amino-5-(2-(cyclohexanecarboxamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(cyclohexanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 37a) as a white powder (78%). ¹H NMR (400 MHz, DMSO-d₆) δ1.11-1.22 (m, 5H), 1.33 (s, 6H), 1.56-1.62 (m, 5H), 2.14 (m, 1H), 2.78(s, 3H), 4.34 (s, 2H), 7.01 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H),7.66 (t, J=8.4 Hz, 1H), 7.74 (s, 1H). MS 400 (MH⁺).

Example 37a ethyl4-amino-5-(2-(cyclohexanecarboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a fromN-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)cyclohexanecarboxamide(Example 37b) and ethyl 3-oxobutanoate as a bright yellow solid (55%).MS 428 (MH⁺).

Example 37bN-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)cyclohexane-carboxamide

Prepared as in Example 22b fromN-(1-hydroxy-2-methylpropan-2-yl)cyclohexane-carboxamide (Example 37c)and 2-amino-6-fluorobenzonitrile as an off-white solid (29%). MS 316(MH⁺).

Example 37c N-(1-hydroxy-2-methylpropan-2-yl)cyclohexanecarboxamide

Prepared as in Example 24a from cyclohexanecarboxylic acid and2-amino-2-methylpropan-1-ol as a colorless oil (15%). MS 200 (MH⁺).

Example 384-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

To a solution of4-amino-5-(2-(3-(2-(benzyloxy)ethoxy)-5-methoxybenzamido)-2-methy-lpropoxy)-2-methylquinoline-3-carboxylicacid (Example 38a, 237 mg, 0.5 mmol) in EtOH/EtOAc (1:1, 20 mL) wasadded 10% Pd/C (wet, 50 mg). The suspension was then stirred under anatmosphere of hydrogen at room temperature overnight. The Pd/C wasfiltered off, and the filtrate was concentrated. The residue waspurified by HPLC (eluent: 10-100% MeOH in H₂O) to give the titlecompound as an off-white solid (152 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆)δ 1.49 (s, 6H), 2.75 (s, 3H), 3.68 (t, J=5.2 Hz, 2H), 3.73 (s, 3H), 3.99(t, J=5.2 Hz, 1H), 4.47 (s, 2H), 6.57 (s, 1H), 6.88 (s, 1H), 6.96 (s,1H), 7.06 (d, J=7.6 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.67 (t, J=8 Hz, 1H),8.14 (s, 1H). MS 484 (MH⁺).

Example 38a4-amino-5-(2-(3-(2-(benzyloxy)ethoxy)-5-methoxybenzamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 38b) as a white powder (95%). MS 574 (MH⁺).

Example 38b ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3-(2-(benzyloxy)ethoxy)-5-methoxybenzoic acid (Example39c) as a pale-brown solid (90%). MS 602 (MH⁺).

Example 38c 3-(2-(benzyloxy)ethoxy)-5-methoxybenzoic

Prepared as in Example 1 from methyl3-(2-(benzyloxy)ethoxy)-5-methoxybenzoate (Example 38d) as a white solid(64%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.83 (s, 3H), 3.84 (t, J=4.8 Hz, 2H),4.18 (t, J=4.8 Hz, 2H), 4.65 (s, 2H), 6.74 (s, 1H), 7.25-7.37 (m, 7H).

Example 38d methyl 3-(2-(benzyloxy)ethoxy)-5-methoxybenzoate

To a solution of methyl 3-hydroxy-5-methoxybenzoate (Chakraporty, T. K.and Reddy, G. V. J. Org. Chem, 57, 1992, 5462.) (3.3 g, 18.1 mmol) indry DMF (30 mL) was added K₂CO₃ (6.3 g, 45.3 mmol) at room temperature.The reaction was stirred at room temperature for 10 minutes then((2-bromoethoxy)methyl)benzene (3.4 mL, 21.7 mmol) was added and themixture stirred at 160° C. for 2 hrs. The reaction was cooled down toroom temperature and diluted with EtOAc, washed with water and brine,and dried over MgSO4, filtered and concentrated to give the crudeproduct (90%) which was used in the next step without furtherpurification.

Example 394-amino-5-((2-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((2-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 39a) as a white powder (90%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.83(d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.42 (m, 3H), 1.65 (m, 4H),1.96 (m, 1H), 2.40 (m, 1H), 2.76 (s, 3H), 4.13 (m, 1H), 4.99 (m, 1H),7.07 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.63 (t, J=8 hz, 1H),7.93 (d, J=7.6 Hz, 1H). MS 386 (MH⁺).

Example 39a ethyl4-amino-5-((2-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a fromN-(2-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyr-amide (Example 39b) andethyl 3-oxobutanoate as a yellow solid (63%). MS 414 (MH⁺).

Example 39b N-(2-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide

Prepared as in Example 22b from N-(2-hydroxycyclohexyl)isobutyramide(Example 39c) and 2-amino-6-fluorobenzonitrile as a brown solid (70%).MS 302 (MH⁺).

Example 39c N-(2-hydroxycyclohexyl)isobutyramide

Prepared as in Example 24a from isobutyric acid and 2-aminocyclohexanolas a colorless oil (53%). MS 186 (MH⁺).

Example 404-amino-5-((4-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((4-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 40a) as a white powder (87%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.97(d, J=7.2 Hz, 6H), 1.34-1.37 (m, 2H), 1.65-1.68 (m, 2H), 1.81-1.84 (m,2H), 2.13-2.16 (m, 2H), 2.33 (m, 1H), 2.75 (s, 3H), 3.58 (m, 1H), 4.84(m, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 7.65 (d, J=7.6Hz, 2H). MS 386 (MH⁺).

Example 40a ethyl4-amino-5-((4-isobutyramidocyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a fromN-(4-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyr-amide (Example 40b) andethyl 3-oxobutanoate as a yellow solid (57%). MS 414 (MH⁺).

Example 40b N-(4-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide

Prepared as in Example 22b from N-(4-hydroxycyclohexyl)isobutyramide(Example 40c) and 2-amino-6-fluorobenzonitrile as an off-white solid(99%). MS 302 (MH⁺).

Example 40c N-(4-hydroxycyclohexyl)isobutyramide

Prepared as in Example 24a from isobutyric acid and 4-aminocyclohexanolas a colorless oil (44%). MS 186 (MH⁺).

Example 41 4-amino-5-isobutoxy-2-methylquinoline-3-carboxylic acid

To a solution of ethyl4-amino-5-isobutoxy-2-methylquinoline-3-carboxylate (Example 41a, 18.0g, 59.53 mmol) in EtOH (150 mL) was added aqueous NaOH solution (3 N, 50mL) and the reaction mixture was refluxed overnight. It was then cooleddown to room temperature and the solution was filtered to remove anypossible solid residue. The filtrate was carefully neutralized with 6NHCl to pH 7 at 0° C. The resultant precipitate was collected byfiltration, washed with water, re-dissolved in EtOH (700 mL) and water(20 mL), and treated with activated charcoal (650 mg) at 70° C. for 0.5h. The charcoal was removed by filtration, and the filtrate wasconcentrated and stored at 4° C. overnight. The resulting precipitatewas collected by filtration, washed with cold H₂O, and dried undervacuum at 60° C. overnight to give the title compound as a white solid(4.24 g, 26%). M.p.: 203.7° C. ¹H NMR (400 MHz, DMSO-d₆) δ 1.01-1.02 (m,6H), 2.19-2.24 (m, 1H), 2.77 (s, 3H), 4.05 (d, J=6.4 Hz, 2H), 7.08 (d,J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 8.9 (brs,1H), 11.45 (brs, 1H), 13.2 (brs, 1H). MS 275 (MH⁺). Elemental AnalysisCalculated (Found) for C₁₅H₁₈N₂O₃.0.75H₂O: C, 62.59% (62.23%); H, 6.83%(7.25%); N, 9.76% (9.73%).

Example 41a ethyl 4-amino-5-isobutoxy-2-methylquinoline-3-carboxylate

To a solution of 2-amino-6-isobutoxybenzonitrile (Example 41b, 16.4 g,86.32 mmol) and ethyl acetoacetate (10.9 mL, 86.32 mmol) in anhydroustoluene (200 mL) was added SnCl₄ (19.9 mL, 172.63 mmol) over a period of15 minutes at room temperature under nitrogen. The stirred reactionmixture was then refluxed for 3.5 h under nitrogen. After it was cooleddown to room temperature, the reaction solution was concentrated toremove most of the solvent under reduced pressure. The residue wasre-dissolved in EtOAc (3 L) and carefully neutralized to pH 8 withaqueous NaOH solution (6.0 N, ˜110 mL) at 0° C. The resultant mixturewas stirred at room temperature overnight. The precipitate was filteredoff, and the organic layer was separated and washed with brine (400 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel eluting with 50%EtOAc in hexanes to give the title compound as a white solid (18.0 g,69%). MS 303 (MH⁺).

Example 41b 2-amino-6-isobutoxybenzonitrile

To a solution of 2-isobutoxy-6-nitrobenzonitrile (Example 41c, 34.3 g,0.156 mol) in AcOH/THF (1:1 by volume, 250 mL) was added iron powder(17.36 g, 0.311 mol) in one portion. The stirred suspension was heatedto reflux for 30 minutes. After it was cooled down to room temperature,the reaction solution was diluted with EtOAc (1 L). The solid wasremoved by filtration, and the filtrate was washed subsequently withwater (300 mL×2), 1N NaOH (300 mL), saturated Na₂CO₃ aqueous solution(300 mL), brine (300 mL), and dried over Na₂SO₄. After evaporation ofthe solvent, the residue was purified by chromatography on silica geleluting with 20% EtOAc in hexanes to give the title compound as a yellowoil (16.4 g, 83%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.96 (d, J=6.8 Hz, 6H),1.96-2.02 (m, 1H), 3.75 (d, J=6.4 Hz, 2H), 5.96 (s, 2H), 6.17 (d, J=8.4Hz, 1H), 6.30 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.8 Hz, 1H). MS 191 (MH⁺).

Example 41b alternative procedure 2-amino-6-isobutoxybenzonitrile

Sodium hydride (60% suspension in oil, 25.0 g, 0.625 mol) was suspendedin anhydrous THF (1000 mL) under nitrogen and heated to an internaltemperature of 40° C. to 45° C. 2-methylpropan-1-ol (61.2 mL, 0.661 mol)was then added slowly and portionwise. The mixture was heated at 40° C.to 45° C. for 1 hour, then cooled to 35° C. 2-amino-6-fluorobenzonitrile(50.0 g, 0.367 mol) was added and refluxed for 21 hours. The mixture wascooled to r.t., then ice (250 g), ice water (750 mL), and hexanes (1000mL) was added. Insoluble solids were filtered out and the organic layerwas separated. The aqueous layer was extracted once more with a mixtureof diethyl ether (250 mL) and hexanes (250 mL). The combined organiclayer was washed twice with a solution of citric acid (53 g) in water(500 mL), then washed with 80% brine (300 mL), then dried with magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas dissolved in methanol (500 mL), and the immiscible oil carriedthrough from the sodium hydride suspension was separated off in aseparatory funnel. The solvent was evaporated under vacuum, and theresidue was washed with hexanes (250 mL), after which the product2-amino-6-isobutoxybenzonitrile was obtained as a viscous oil (46 grams,yield: 66%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (t, J=8.0 Hz, 1H), 6.33(d, J=8.0 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 5.97 (s, 2H), 3.75 (d, J=7.2Hz, 2H), 2.00 (m, 1H), 0.97 (d, J=6.8 Hz, 6H) ppm. MS 191 (MH⁺).

Example 41c 2-isobutoxy-6-nitrobenzonitrile

To a solution of 2-methylpropan-1-ol (9.6 mL, 0.104 mol) in anhydrousTHF (200 mL) was added NaH (60% in mineral oil, 4.565 g, 0.114 mol) insmall portions at 0° C. under N₂. After it was stirred at roomtemperature for 30 min, the reaction mixture was cooled down to −70° C.and 2,6-dinitrobenzonitrile (20.0 g, 0.104 mol) was added portionwise.After the addition was complete, the reaction mixture was stirred at−70° C.-RT overnight, then poured into ice water (600 mL). The resultantprecipitate was collected by filtration and rinsed with water, hexane,and air dried to provide 2-isobutoxy-6-nitrobenzonitrile as a lightyellow solid (34.3 g, 100%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.0 (d, J=6.8Hz, 6H), 2.04-2.11 (m, 1H), 4.02 (d, J=6.8 Hz, 2H), 7.69-7.71 (m, 1H),7.84-7.90 (m, 2H). MS 221 (MH⁺).

Example 42 4-amino-5-isopropoxy-2-methylquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-5-isopropoxy-2-methylquinoline-3-carboxylate (Example 42a) as awhite solid (71%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.4 (d, J=6.4 Hz, 6H),2.73 (s, 3H), 4.87-4.93 (m, 1H), 7.01 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0Hz, 1H), 7.60 (t, J=8.4 Hz, 1H). MS 261 (MH⁺).

Example 42a ethyl 4-amino-5-isopropoxy-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-isopropoxybenzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as an off-white solid (32%). ¹H NMR (400 MHz, DMSO-d₆) δ1.32 (t, J=7.6 Hz, 3H), 1.38 (d, J=6.0 Hz, 6H), 2.54 (s, 3H), 4.3 (q,J=7.2 Hz, 2H), 4.83-4.89 (m, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 8.14 (s, 2H). MS 289 (MH⁺).

Example 434-amino-5-((1-(hydroxymethyl)cyclohexyl)methoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((1-(hydroxymethyl)cyclohexyl)-methoxy)-2-methylquinoline-3-carboxylate(Example 43a) as an off-white solid (49%). ¹H NMR (400 MHz, DMSO-d₆) δ1.37-1.48 (m, 10H), 2.75 (s, 3H), 3.50 (s, 2H), 4.03 (s, 2H), 5.08 (brs,1H), 7.06 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.66 (t, J=8.4 Hz,1H), 9.39 (brs, 1H), 12.17 (brs, 1H), 12.74 (brs, 1H). MS 345 (MH⁺).

Example 43a ethyl4-amino-5-((1-(hydroxymethyl)cyclohexyl)methoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 2a from(1-((3-amino-2-cyanophenoxy)methyl)cyclohexyl)-methyl acetate(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as an off-white solid (60%). MS 373 (MH⁺).

Example 444-amino-5-(2-(3,5-dihydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 44a) as a white solid (73%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.46(s, 6H), 2.75 (s, 3H), 4.44 (s, 2H), 6.3-6.31 (m, 1H), 6.61 (s, 2H),7.04 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H),7.98 (s, 1H), 8.79 (brs, 1H), 9.48 (s, 2H). MS 426 (MH⁺).

Example 44a ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 24b) and 3,5-dihydroxybenzoic acid as a yellow-brown solid(15%). MS 454 (MH⁺).

Example 454-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)oxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)-oxy)-2-methylquinoline-3-carboxylate(Example 45a) as a white powder (71%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.01(d, J=6.4 Hz, 6H), 1.59-1.68 (m, 6H), 2.06-2.09 (m, 2H), 2.2-2.22 (m,1H), 2.76 (s, 3H), 3.77-3.83 (m, 1H), 4.96 (s, 1H), 7.06 (d, J=8.0 Hz,1H), 7.26 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.4 Hz,1H), 8.79 (brs, 1H), 12.84 (brs, 2H). MS 386 (MH⁺).

Example 45a ethyl4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)oxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 2a from4-(3-amino-2-cyanophenoxy)-N-isopropylcyclohexane-carboxamide (Example45b) and ethyl 3-oxobutanoate as a yellow solid (56%). MS 414 (MH⁺).

Example 45b 4-(3-amino-2-cyanophenoxy)-N-isopropylcyclohexanecarboxamide

Prepared as in Example 22b from4-hydroxy-N-isopropylcyclohexanecarboxamide (Example 45c) and2-amino-6-fluorobenzonitrile as an off-white solid (17%). ¹H NMR (400MHz, DMSO-d₆) δ 1.01 (d, J=6.4 Hz, 6H), 1.47-1.57 (m, 4H), 1.67-1.77 (m,2H), 1.89-1.93 (m, 2H), 2.08-2.15 (m, 1H), 3.75-3.84 (m, 1H), 4.57 (brs,1H), 5.93 (s, 2H), 6.19 (d, J=8.0 Hz, 1H), 6.28 (d, J=8.0 Hz, 1H), 7.13(t, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H). MS 302 (MH⁺).

Example 45c 4-hydroxy-N-isopropylcyclohexanecarboxamide

Prepared as in Example 24a from 4-hydroxycyclohexanecarboxylic acid andpropan-2-amine as a colorless oil (68%). MS 186 (MH⁺).

Example 464-amino-5-(3-((3-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-((3-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 46a) as a white powder (58%). M.p.: 172˜174° C. ¹H NMR (400MHz, DMSO-d₆) δ 1.31 (s, 6H), 2.76 (s, 3H), 3.53 (s, 3H), 4.21 (s, 2H),4.27 (d, J=5.6 Hz, 2H), 6.64 (dd, J=8.0, 2.4 Hz, 1H), 6.69 (m, 1H), 6.72(d, J=8.0 Hz, 1H), 6.98-7.10 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.66 (t,J=8.0 Hz, 1H), 8.47 (t, J=5.6 Hz, 1H), 8.77 (brs, 1H), 12.26 (brs, 1H),12.79 (brs, 1H). MS 438 (MH⁺).

Example 46a ethyl4-amino-5-(3-((3-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)-N-(3-methoxybenzyl)-2,2-dimethylpropanamide(Example 46b) and ethyl 3-oxobutanoate as a yellow solid (42%). MS 466(MH⁺).

Example 46b3-(3-amino-2-cyanophenoxy)-N-(3-methoxybenzyl)-2,2-dimethylpropanamide

Prepared as in Example 22b from3-hydroxy-N-(3-methoxybenzyl)-2,2-dimethyl-propanamide (Example 46c) and2-amino-6-fluorobenzonitrile as a white solid (41%). MS 354 (MH⁺).

Example 46c 3-hydroxy-N-(3-methoxybenzyl)-2,2-dimethylpropanamide

Prepared as in Example 24a from 3-hydroxy-2,2-dimethylpropanoic acid and(3-methoxyphenyl)methanamine as an orange oil (41%). MS 238 (MH⁺).

Example 474-amino-5-(3-(cyclohexylamino)-2,2-dimethyl-3-oxopropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cyclohexylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 47a) as an off-white solid (13%). MS 400 (MH⁺).

Example 47a ethyl4-amino-5-(3-(cyclohexylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cyclohexanamine as a yellow-brown solid (46%). MS428 (MH⁺).

Example 47b3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid

Prepared as in Example 2a from benzyl3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-propanoate (Example 47c) andethyl 3-oxobutanoate as a brown solid (80%). MS 192 (MH⁺).

Example 47c 3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropanoate

To a solution of benzyl3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropanoate (Example 47d, 200 mg,0.56 mmol) in AcOH (5 mL) was added iron powder (158 mg, 2.82 mmol) atroom temperature. The reaction mixture was then stirred at 90° C. for 1h. The reaction mixture was cooled to room temperature then diluted withAcOEt. The precipitate was filtered off and the filtrate wassuccessively washed with 1 N NaOH and brine, then dried over Na₂SO₄,filtered and evaporated. The residue was purified by chromatography onsilica gel (eluent: 40% EtOAc in hexanes) to give a title compound as acolorless oil (187 mg, 100%). MS 325 (MH⁺).

Example 47d benzyl 3-(2-cyano-3-nitrophenoxy)-2,2-dimethylpropanoate

To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. etal. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF(200 mL) was carefully added NaH (60% in mineral oil, 3.5 g, 87.5 mmol)in small portions at 0° C. under nitrogen. The reaction mixture wasstirred at 0° C. under nitrogen for 2 hrs. To this solution was added2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol), and the reaction solutionwas stirred at 0° C.-RT under nitrogen overnight. The reaction mixturewas quenched with brine, and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried over Na₂SO₄. Afterevaporation of the solvent, the residue was purified by chromatographyon silica gel eluting (Elunet: 20% EtOAc in hexanes) to give the titlecompound as a brown solid (10.0 g, 87%). MS 355 (MH⁺).

Example 484-amino-5-(3-(cycloheptylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquino-line-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cycloheptylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 48a) as an off-white solid (12%). MS 414 (MH⁺).

Example 48a ethyl4-amino-5-(3-(cycloheptylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cycloheptanamine as a brown solid (43%). MS 456(MH⁺).

Example 494-amino-5-(3-(cyclooctylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquino-line-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-(cyclooctylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 49a) as an off-white solid (11%). MS 428 (MH⁺).

Example 49a ethyl4-amino-5-(3-(cyclooctylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and cyclooctanamine as a brown solid (46%). MS 456(MH⁺).

Example 504-amino-5-(3-((3-hydroxy-2,2-dimethylpropyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-((3-hydroxy-2,2-dimethylpropyl)-amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 50a) as an off-white solid (87%). ¹H NMR (400 MHz, DMSO-d₆) δ0.71 (s, 6H), 1.28 (s, 6H), 2.74 (s, 3H), 2.97 (d, J=6.0 Hz, 2H), 3.0(s, 2H), 4.57 (brs, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H),7.65 (t, J=8.4 Hz, 1H), 7.77 (t, J=6.4 Hz, 1H), 8.78 (brs, 1H), 12.04(brs, 1H), 12.82 (brs, 1H). MS 404 (MH⁺).

Example 50a ethyl4-amino-5-(3-((3-hydroxy-2,2-dimethylpropyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and 3-amino-2,2-dimethylpropan-1-ol as a brown solid(40%). MS 432 (MH⁺).

Example 514-amino-5-(3-(chroman-4-ylamino)-2,2-dimethyl-3-oxopropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-(chroman-4-ylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 51a) as an off-white solid (80%). ¹H NMR (400 MHz, DMSO-d₆) δ1.31 (d, J=4.0 Hz, 6H), 1.80-2.00 (m, 2H), 2.76 (s, 3H), 4.05-4.19 (m,2H), 4.24 (s, 2H), 5.10 (q, J=6.8 Hz, 1H), 6.51 (t, J=7.6 Hz, 1H), 6.89(d, J=8.4 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 7.01 (dd, J=15.0, 8.4 Hz,2H), 7.30 (d, J=8.8 Hz, 1H), 7.66 (t, J=8.4 Hz, 1H), 8.26 (d, J=8.8 Hz,1H), 8.77 (brs, 1H), 12.31 (brs, 1H), 12.86 (brs, 1H). MS 450 (MH⁺).

Example 51a ethyl4-amino-5-(3-(chroman-4-ylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and chroman-4-amine (Lu, Y. et al. PCT Int. Appl.2008, WO 2008043019) as a brown solid (37%). MS 478 (MH⁺).

Example 524-amino-5-(3-((5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-((5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 52a) as an off-white solid (69%). ¹H NMR (400 MHz, DMSO-d₆) δ1.30 (d, J=4.0 Hz, 6H), 1.52-1.87 (m, 4H), 2.75 (s, 3H), 4.22 (s, 2H),4.95-5.05 (m, 1H), 6.59 (d, J=7.2 Hz, 1H), 6.67-6.75 (m, 2H), 6.97 (d,J=8.4 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.64 (t, J=8.4 Hz, 1H), 8.13 (d,J=8.8 Hz, 1H), 8.74 (brs, 1H), 12.22 (brs, 1H), 12.80 (brs, 1H). MS 478(MH⁺).

Example 52a ethyl4-amino-5-(3-((5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and 5-methoxy-1,2,3,4-tetrahydronaphtha-len-1-amineas a brown solid (40%). MS 506 (MH⁺).

Example 534-amino-5-(2-(4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-methoxybenzamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylate(Example 53a) as a white solid. MS 424 (MH⁺).

Example 53a ethyl4-amino-5-(2-(4-methoxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 4-methoxybenzoic acid as a brown solid. MS 452 (MH⁺).

Example 544-amino-5-(2-(2-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-hydroxybenzamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate(Example 54a) as an off-white solid. MS 410 (MH⁺).

Example 54a ethyl4-amino-5-(2-(2-hydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 2-hydroxybenzoic acid as a brown solid. MS 438 (MH⁺).

Example 554-amino-5-(2-(3-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-methoxybenzamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylate(Example 55a) as a white solid. MS 424 (MH⁺).

Example 55a ethyl4-amino-5-(2-(3-methoxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3-methoxybenzoic acid as a brown solid. MS 452 (MH⁺).

Example 564-amino-5-(2-benzamido-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-benzamido-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 56a) as a white solid. MS 394 (MH⁺).

Example 56a ethyl4-amino-5-(2-benzamido-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and benzoic acid as a brown solid. MS 422 (MH⁺).

Example 574-amino-5-(2-(4-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-hydroxybenzamido)-2-methylprop-oxy)-2-methylquinoline-3-carboxylate(Example 57a) as an off-white solid. MS 410 (MH⁺).

Example 57a ethyl4-amino-5-(2-(4-hydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 4-hydroxybenzoic acid as a brown solid. MS 438 (MH⁺).

Example 584-amino-5-(2-(2-fluorobenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-fluorobenzamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate(Example 58a) as an off-white solid. MS 412 (MH⁺).

Example 58a ethyl4-amino-5-(2-(2-fluorobenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 2-fluorobenzoic acid as a brown solid. MS 440 (MH⁺).

Example 594-amino-5-(2-(3-fluorobenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-fluorobenzamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylate(Example 59a) as an off-white solid. MS 412 (MH⁺).

Example 59a ethyl4-amino-5-(2-(3-fluorobenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3-fluorobenzoic acid as a brown solid. MS 440 (MH⁺).

Example 604-amino-5-(2-(3-hydroxy-4-methoxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-hydroxy-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 60a) as an off-white solid. MS 440 (MH⁺).

Example 60a ethyl4-amino-5-(2-(3-hydroxy-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3-hydroxy-4-methoxybenzoic acid as a brown solid. MS468 (MH⁺).

Example 614-amino-5-(2-(3-carbamoylbenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-carbamoylbenzamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate(Example 61a) as an off-white solid. MS 437 (MH⁺).

Example 61a ethyl4-amino-5-(2-(3-carbamoylbenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3-carbamoylbenzoic acid as a brown solid. MS 465(MH⁺).

Example 624-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 62a) as a pale-yellow solid (18%). ¹H NMR (400 MHz, DMSO-d₆) δ1.49 (s, 6H), 2.76 (s, 3H), 4.25 (m, 4H), 4.48 (s, 2H), 6.87 (d, J=8.8Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.39-7.26 (m, 3H), 7.67 (t, J=7.2 Hz,1H), 7.99 (s, 1H), 8.83 (brs, 1H), 12.31 (brs, 1H), 12.71 (brs, 1H). MS452 (MH⁺).

Example 62a ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as abrown solid (60%). MS 480 (MH⁺).

Example 634-amino-5-(2-(2-ethylbutanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-ethylbutanamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate(Example 63a) as an off-white solid. MS 388 (MH⁺).

Example 63a ethyl4-amino-5-(2-(2-ethylbutanamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 2-ethylbutanoic acid as a brown solid. MS 416 (MH⁺).

Example 644-amino-5-(2-(3-methoxypropanamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-methoxypropanamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate(Example 64a) as an off-white solid. MS 376 (MH⁺).

Example 64a ethyl4-amino-5-(2-(3-methoxypropanamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3-methoxypropanoic acid as a brown solid. MS 404(MH⁺).

Example 654-amino-5-(2-butyramido-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-butyramido-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 65a) as an off-white solid. MS 360 (MH⁺).

Example 65a ethyl4-amino-5-(2-butyramido-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and butyric acid as a brown solid. MS 388 (MH⁺).

Example 664-amino-2-methyl-5-(2-methyl-2-(tetrahydrofuran-3-carboxamido)propoxy)-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-(2-methyl-2-(tetrahydrofuran-3-carboxamido)propoxy)quinoline-3-carboxylate(Example 66a) as an off-white solid. MS 388 (MH⁺).

Example 66a ethyl4-amino-2-methyl-5-(2-methyl-2-(tetrahydrofuran-3-carboxamido)-propoxy)quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and tetrahydrofuran-3-carboxylic acid as a brown solid. MS416 (MH⁺).

Example 674-amino-5-(2-(4-(hydroxymethyl)benzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-(hydroxymethyl)benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 67a) as an off-white solid. MS 424 (MH⁺).

Example 67a ethyl4-amino-5-(2-(4-(hydroxymethyl)benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 4-(hydroxymethyl)benzoic acid as a brown solid. MS 452(MH⁺).

Example 684-amino-5-(2-(2-methoxyacetamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-methoxyacetamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylate(Example 68a) as an off-white solid. MS 362 (MH⁺).

Example 68a ethyl4-amino-5-(2-(2-methoxyacetamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 2-methoxyacetic acid as a brown solid. MS 390 (MH⁺).

Example 695-(2-acetamido-2-methylpropoxy)-4-amino-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl5-(2-acetamido-2-methylpropoxy)-4-amino-2-methylquinoline-3-carboxylate(Example 69a) as an off-white solid. MS 332 (MH⁺).

Example 69a ethyl5-(2-acetamido-2-methylpropoxy)-4-amino-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and acetic acid as a brown solid. MS 390 (MH⁺).

Example 704-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 70a) as an off-white solid. MS 452 (MH⁺).

Example 70a ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as abrown solid. MS 480 (MH⁺).

Example 714-amino-5-(2-(3,5-dimethoxybenzamido)-2-methylpropoxy)-2-methylquino-line-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3,5-dimethoxybenzamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate(Example 71a) as an off-white solid. MS 454 (MH⁺).

Example 71a ethyl4-amino-5-(2-(3,5-dimethoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3,5-dimethoxybenzoic acid as a brown solid. MS 482(MH⁺).

Example 724-amino-5-(2-(3,4-dimethoxybenzamido)-2-methylpropoxy)-2-methylquino-line-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3,4-dimethoxybenzamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate(Example 72a) as an off-white solid. MS 454 (MH⁺).

Example 72a ethyl4-amino-5-(2-(3,4-dimethoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3,4-dimethoxybenzoic acid as a brown solid. MS 482(MH⁺).

Example 734-amino-5-(2-(2-(4-methoxyphenyl)acetamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(2-(4-methoxyphenyl)acetamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 73a) as an off-white solid. MS 438 (MH⁺).

Example 73a ethyl4-amino-5-(2-(2-(4-methoxyphenyl)acetamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 2-(3,4-dimethoxyphenyl)acetic acid as a brown solid.MS 466 (MH⁺).

Example 744-amino-5-(2-(4-fluoro-3-hydroxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-fluoro-3-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 74a) as an off-white solid. MS 428 (MH⁺).

Example 74a ethyl4-amino-5-(2-(4-fluoro-3-hydroxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 4-fluoro-3-hydroxybenzoic acid as a brown solid. MS456 (MH⁺).

Example 754-amino-5-(2-(3-hydroxy-5-methoxybenzamido)-2-methylpropoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-hydroxy-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 75a) as an off-white solid. MS 440 (MH⁺).

Example 75a ethyl4-amino-5-(2-(3-hydroxy-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3-hydroxy-5-methoxybenzoic acid as a brown solid. MS468 (MH⁺).

Example 764-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 76a) as an off-white solid. MS 484 (MH⁺).

Example 76a ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)-2-methyl-propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. etal. Bioorg. Med. Chem. Lett. 2009, 19, 4151.) as a brown solid. MS 512(MH⁺).

Example 774-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 77a) as an off-white solid. MS 484 (MH⁺).

Example 77a ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3-(2-hydroxyethoxy)-4-methoxybenzoic acid as a brownsolid. MS 512 (MH⁺).

Example 784-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 78a) as an off-white solid. MS 498 (MH⁺).

Example 78a ethyl4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 3-(3-hydroxypropoxy)-4-methoxybenzoic acid as a brownsolid. MS 526 (MH⁺).

Example 794-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxy-benzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate(Example 79a) as an off-white solid. MS 498 (MH⁺).

Example 79a ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from4-amino-5-(2-amino-2-methylpropoxy)-2-methylquino-line-3-carboxylate(Example 24b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi,P. G. et al. J. Med. Chem. 1999, 42, 5131.) as a brown solid. MS 526(MH⁺).

Example 80(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)propoxy)-2-methylquinoline-3-carboxylate(Example 80a) as an off-white solid. MS 438 (MH⁺).

Example 80a (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brownsolid. MS 466 (MH⁺).

Example 81(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)propoxy)-2-methylquinoline-3-carboxylate(Example 81a) as an off-white solid. MS 438 (MH⁺).

Example 81a (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as brownsolid. MS 466 (MH⁺).

Example 82(S)-4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 82a) as an off-white solid. MS 470 (MH⁺).

Example 82a (S)-ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al.Bioorg. Med. Chem. Lett. 2009, 19, 4151.) as a brown solid. MS 498(MH⁺).

Example 83(S)-4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 83a) as an off-white solid. MS 470 (MH⁺).

Example 83a (S)-ethyl4-amino-5-(2-(3-(2-hydroxyethoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 3-(2-hydroxyethoxy)-4-methoxybenzoic acid as a brown solid. MS498 (MH⁺).

Example 84(S)-4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 84a) as an off-white solid. MS 484 (MH⁺).

Example 84a (S)-ethyl4-amino-5-(2-(3-(3-hydroxypropoxy)-4-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 3-(3-hydroxypropoxy)-4-methoxybenzoic acid as a brown solid. MS512 (MH⁺).

Example 85(S)-4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 85a) as an off-white solid. MS 484 (MH⁺).

Example 85a (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example26b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. etal. J. Med. Chem. 1999, 42, 5131.) as a brown solid. MS 512 (MH⁺).

Example 86(R)-4-amino-5-(2-(cyclohexanecarboxamido)propoxy)-2-methylquinoline-3-carboxylicacid (SID 47687595)

Prepared as in Example 1 from (R)-ethyl4-amino-5-(2-(cyclohexanecarboxamido)-propoxy)-2-methylquinoline-3-carboxylate(Example 86a) as a white solid (43%). ¹H NMR (400 MHz, DMSO-d₆) δ1.25-1.10 (m, 5H), 1.34-1.31 (m, 2H), 1.69-1.62 (m, 5H), 2.11-2.05 (m,1H), 2.69 (s, 3H), 3.93 (t, J=9.2 Hz, 1H), 4.13 (dd, J=4, 9.6 Hz, 1H),4.14-4.11 (m, 1H), 6.86 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.49(t, J=8.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H). MS 386 (MH⁺).

Example 86a (R)-ethyl4-amino-5-(2-(cyclohexanecarboxamido)propoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example86b) and cyclohexanecarboxylic acid as brown solid (31%). MS 414 (MH⁺).

Example 86b (R)-ethyl4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from (R)-benzyl(1-(3-amino-2-cyanophenoxy)propan-2-yl)-carbamate (Example 86c) andethyl 3-oxobutanoate as brown solid. MS 304 (MH⁺).

Example 86c (R)-benzyl (1-(3-amino-2-cyanophenoxy)propan-2-yl)carbamate

Prepared as in Example 24c from(R)-2-amino-6-(2-aminopropoxy)benzonitrile (Example 86d) as brown solid(79%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.12 (d, J=6.4 Hz, 3H), 3.81 (d,J=8.4 Hz, 1H), 3.95-3.92 (m, 1H), 4.99 (s, 2H), 5.36 (s, 2H), 5.96 (s,2H), 6.20 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.13 (t, J=8.4 Hz,1H), 7.44-7.38 (m, 5H). MS 326 (MH⁺).

Example 86d (R)-2-amino-6-(2-aminopropoxy)benzonitrile

Prepared as in Example 24d from (R)-2-aminopropan-1-ol and2-amino-6-fluoro-benzonitrile as brown solid (81%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.01 (d, J=6.5 Hz, 3H), 3.08 (m, 1H), 3.71 (d, J=6.1 Hz, 2H),5.95 (s, 2H), 6.15 (d, J=8.3 Hz, 1H), 6.2 (d, J=8.3 Hz, 1H), 7.13 (t,J=8.3 Hz, 1H). MS 192 (MH⁺).

Example 87(R)-4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (R)-ethyl4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylate(Example 87a) as an off-white solid (32%). ¹H NMR (400 MHz, DMSO-d₆) δ1.31 (d, J=6.8 Hz, 3H), 2.66 (s, 3H), 4.14 (t, J=9.2 Hz, 1H), 4.28 (dd,J=3.6, 9.6 Hz, 1H), 4.70-4.55 (m, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.26 (d,J=8.4 Hz, 1H), 7.51 (t, J=8.4 Hz, 1H), 7.75 (dd, J=1.2, 6.0 Hz, 2H),8.71 (dd, J=1.2, 6.0 Hz, 2H), 8.95 (d, J=8.0 Hz, 1H). MS 409 (MH⁺).

Example 87a (R)-ethyl4-amino-5-(2-(isonicotinamido)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example86b) and isonicotinic acid as brown solid (41%). MS 409 (MH⁺).

Example 88(R)-4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (R)-ethyl4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquinoline-3-carboxylate(Example 88a) as a white solid (51%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.28(d, J=7.2 Hz, 3H), 2.65 (s, 3H), 4.11 (t, J=8.8 Hz, 1H), 4.22 (dd,J=4.0, 10 Hz, 1H), 4.65-4.55 (m, 1H), 6.88 (d, J=8.0, 2H), 7.25-7.13 (m,4H), 7.48 (t, J=8.0 Hz, 1H), 8.49 (d, J=8.0, 1H), 9.93 (brs, 1H). MS 396(MH⁺).

Example 88a (R)-ethyl4-amino-5-(2-(3-hydroxybenzamido)propoxy)-2-methylquino-line-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example86b) and 3-hydroxybenzoic acid as brown solid (36%). MS 424 (MH⁺).

Example 89(S)-4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methyl-quinoline-3-carboxylicacid (SID 47039333)

Prepared as in Example 1 from (S)-ethyl4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 89a) as an off-white solid (31%). ¹H NMR (400 MHz, DMSO-d₆) δ1.34-1.11 (m, 5H), 1.72-1.51 (m, 5H), 2.08-1.79 (m, 5H), 2.44-2.35 (m1H), 2.52 (s, 3H), 3.55-3.45 (m, 2H), 4.02 (dd, J=6.8, 9.2 Hz, 1H), 4.17(dd, J=4.8, 10.0 Hz, 1H), 4.45-4.38 (m, 1H), 6.75 (d, J=7.2 Hz), 7.11(d, J=7.6 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H). MS 412 (MH⁺).

Example 89a (S)-ethyl4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 89b) and cyclohexanecarboxylic acid as brown solid (46%). MS440 (MH⁺).

Example 89b (S)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from (S)-benzyl2-((3-amino-2-cyanophenoxy)methyl)pyrro-lidine-1-carboxylate (Example89c) and ethyl 3-oxobutanoate as brown solid. MS 330 (MH⁺).

Example 89c (S)-benzyl2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate

Prepared as in Example 24c from(S)-2-amino-6-(pyrrolidin-2-ylmethoxy)benzonitrile (Example 89d) asbrown solid (79%). MS 351 (MH⁺).

Example 89d (S)-2-amino-6-(pyrrolidin-2-ylmethoxy)benzonitrile

Prepared as in Example 24d from (S)-pyrrolidin-2-ylmethanol and2-amino-6-fluoro-benzonitrile as brown solid (51%). MS 218 (MH⁺).

Example 90(S)-4-amino-5-((1-isobutyrylpyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-((1-isobutyrylpyrrolidin-2-yl)-methoxy)-2-methylquinoline-3-carboxylate(Example 90a) as an off-white solid (39%). ¹H NMR (400 MHz, DMSO-d₆) δ0.99 (dd, J=2.0, 6.8 Hz, 6H), 2.05-1.83 (m, 4H), 2.65 (s, 3H), 3.53 (t,J=7.2 Hz, 2H), 4.08 (dd, J=6.8, 10.0 Hz, 1H), 4.20 (dd, J=6.0, 10.0 Hz,1H), 4.54 (m, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.50(t, J=8.0 Hz, 1H). MS 344 (MH⁺).

Example 90a (S)-ethyl4-amino-5-((1-isobutyrylpyrrolidin-2-yl)-methoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 89b) and isobutyric acid as brown solid (46%). MS 400 (MH⁺).

Example 91(S)-5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylate(Example 91a) as an off-white solid (23%). ¹H NMR (400 MHz, DMSO-d₆) δ1.98 (s, 3H), 2.03-1.82 (m, 4H), 2.71 (s, 3H), 3.48 (t, J=6.0 Hz, 2H),4.05 (dd, J=6.4, 10.0 Hz, 1H), 4.22 (dd, J=6.8, 10.0 Hz, 1H), 4.54-4.46(m, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.54 (t, J=10.0Hz, 1H). MS 344 (MH⁺).

Example 91a (S)-ethyl5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquino-line-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 89b) and acetic anhydride as brown solid (31%). MS 372 (MH⁺).

Example 92(R)-4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from (R)-ethyl4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 92a) as an off-white solid (37%). ¹H NMR (400 MHz, DMSO-d₆) δ1.34-1.11 (m, 5H), 1.72-1.51 (m, 5H), 2.08-1.79 (m, 5H), 2.44-2.35 (m1H), 2.52 (s, 3H), 3.55-3.45 (m, 2H), 4.02 (dd, J=6.8, 9.2 Hz, 1H), 4.17(dd, J=4.8, 10.0 Hz, 1H), 4.45-4.38 (m, 1H), 6.75 (d, J=7.2 Hz), 7.11(d, J=7.6 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H). MS 412 (MH⁺).

Example 92a (R)-ethyl4-amino-5-((1-(cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 92b) and cyclohexanecarboxylic acid as brown solid (39%). MS440 (MH⁺).

Example 92b (R)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from (R)-benzyl2-((3-amino-2-cyanophenoxy)methyl)pyrro-lidine-1-carboxylate (Example92c) and ethyl 3-oxobutanoate as brown solid. MS 330 (MH⁺).

Example 92c (R)-benzyl2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate

Prepared as in Example 24c from(R)-2-amino-6-(pyrrolidin-2-ylmethoxy)benzonitrile (Example 92d) asbrown solid (71%). MS 351 (MH⁺).

Example 92d (R)-2-amino-6-(pyrrolidin-2-ylmethoxy)benzonitrile

Prepared as in Example 24d from (R)-pyrrolidin-2-ylmethanol and2-amino-6-fluoro-benzonitrile as brown solid (57%). MS 218 (MH⁺).

Example 93(R)-4-amino-5-((1-isobutyrylpyrrolidin-2-yl)methoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (R)-ethyl4-amino-5-((1-isobutyrylpyrrolidin-2-yl)-methoxy)-2-methylquinoline-3-carboxylate(Example 93a) as an off-white solid (44%). ¹H NMR (400 MHz, DMSO-d₆) δ0.99 (dd, J=2.0, 6.8 Hz, 6H), 2.05-1.83 (m, 4H), 2.65 (s, 3H), 3.53 (t,J=7.2 Hz, 2H), 4.08 (dd, J=6.8, 10.0 Hz, 1H), 4.20 (dd, J=6.0, 10.0 Hz,1H), 4.54 (m, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.50(t, J=8.0 Hz, 1H). MS 344 (MH⁺).

Example 93a (R)-ethyl4-amino-5-((1-isobutyrylpyrrolidin-2-yl)-methoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate(Example 92b) and isobutyric acid as brown solid (39%). MS 400 (MH⁺).

Example 94(R)-5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (R)-ethyl5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquinoline-3-carboxylate(Example 94a) as an off-white solid (19%). ¹H NMR (400 MHz, DMSO-d₆) δ1.98 (s, 3H), 2.03-1.82 (m, 4H), 2.71 (s, 3H), 3.48 (t, J=6.0 Hz, 2H),4.05 (dd, J=6.4, 10.0 Hz, 1H), 4.22 (dd, J=6.8, 10.0 Hz, 1H), 4.54-4.46(m, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.54 (t, J=10.0Hz, 1H). MS 344 (MH⁺).

Example 94a (R)-ethyl5-((1-acetylpyrrolidin-2-yl)methoxy)-4-amino-2-methylquino-line-3-carboxylate

Prepared as in Example 24a from (R)-ethyl4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)quinoline-3-carboxylate(Example 92b) and acetic anhydride as brown solid (28%). MS 372 (MH⁺).

Example 95(S)-4-amino-5-(2-(2-hydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2-hydroxybenzamido)-3-methyl-butoxy)-2-methylquinoline-3-carboxylate(Example 95a) as a white solid (82%). MS 424 (MH⁺).

Example 95a (S)-ethyl4-amino-5-(2-(2-hydroxybenzamido)-3-methylbutoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 2-hydroxybenzoic acid as brown solid (56%). MS 452(MH⁺).

Example 95b (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from (S)-benzyl1-(3-amino-2-cyanophenoxy)-3-methylbutan-2-ylcarbamate (Example 95c) andethyl 3-oxobutanoate as brown solid (79%). MS 332 (MH⁺).

Example 95c (S)-benzyl1-(3-amino-2-cyanophenoxy)-3-methylbutan-2-ylcarbamate

Prepared as in Example 24c from(S)-2-amino-6-(2-amino-3-methylbutoxy)benzonitrile (Example 95d) asbrown solid (82%). MS 354 (MH⁺).

Example 95d (S)-2-amino-6-(2-amino-3-methylbutoxy)benzonitrile

Prepared as in Example 24d from (S)-2-amino-3-methylbutan-1-ol and2-amino-6-fluoro-benzonitrile as brown solid (71%). MS 220 (MH⁺).

Example 96(S)-4-amino-5-(2-(3-hydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)-3-methyl-butoxy)-2-methylquinoline-3-carboxylate(Example 96a) as a white solid (83%). MS 424 (MH⁺).

Example 96a (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)-3-methylbutoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 3-hydroxybenzoic acid as brown solid (35%). MS 452(MH⁺).

Example 97(S)-4-amino-5-(2-(2-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 97a) as an off-white solid (78%). MS 410 (MH⁺).

Example 97a (S)-ethyl4-amino-5-(2-(2-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquino-line-3-carboxylate (Example 97b)and 2-hydroxybenzoic acid as brown solid (46%). MS 438 (MH⁺).

Example 97b (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from (S)-benzyl1-(3-amino-2-cyanophenoxy)butan-2-ylcarbamate (Example 97c) and ethyl3-oxobutanoate as brown solid (75%). MS 318 (MH⁺).

Example 97c (S)-benzyl 1-(3-amino-2-cyanophenoxy)butan-2-ylcarbamate

Prepared as in Example 24c from(S)-2-amino-6-(2-aminobutoxy)benzonitrile (Example 97d) as brown solid(87%). MS 340 (MH⁺).

Example 97d (S)-2-amino-6-(2-aminobutoxy)benzonitrile

Prepared as in Example 24d from (S)-2-aminobutan-1-ol and2-amino-6-fluoro-benzonitrile as brown solid (73%). MS 206 (MH⁺).

Example 98(S)-4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)butoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxy-benzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 98a) as an off-white solid (83%). MS 484 (MH⁺).

Example 98a (S)-ethyl4-amino-5-(2-(4-(2-hydroxyethoxy)-3-methoxybenzamido)-butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquino-line-3-carboxylate (Example 97b)and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al. Bioorg.Med. Chem. Lett. 2009, 19, 4151.) as brown solid (38%). MS 512 (MH⁺).

Example 99(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)butoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)butoxy)-2-methylquinoline-3-carboxylate(Example 99a) as an off-white solid (78%). MS 452 (MH⁺).

Example 99a (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquino-line-3-carboxylate (Example 97b)and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as brown solid(40%). MS 480 (MH⁺).

Example 100(S)-4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)butoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 100a) as an off-white solid (79%). MS 498 (MH⁺).

Example 100a (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquino-line-3-carboxylate (Example 97b)and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. et al. J.Med. Chem. 1999, 42, 5131.) as brown solid (41%). MS 526 (MH⁺).

Example 101(S)-4-amino-5-(2-(3,5-dihydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 101a) as an off-white solid (69%). MS 426 (MH⁺).

Example 101a (S)-ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)butoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquino-line-3-carboxylate (Example 97b)and 3,5-dihydroxybenzoic acid as brown solid (37%). MS 454 (MH⁺).

Example 102(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)butoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)butoxy)-2-methylquinoline-3-carboxylate(Example 102a) as an off-white solid (71%). MS 452 (MH⁺).

Example 102a (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)butoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquino-line-3-carboxylate (Example 97b)and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brown solid(46%). MS 480 (MH⁺).

Example 103(S)-4-amino-5-(2-(3-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)butoxy)-2-methylquinoline-3-carboxylate(Example 103a) as an off-white solid (72%). MS 410 (MH⁺).

Example 103a (S)-ethyl4-amino-5-(2-(3-hydroxybenzamido)butoxy)-2-methylquino-line-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-aminobutoxy)-2-methylquino-line-3-carboxylate (Example 97b)and 3-hydroxybenzoic acid as brown solid (49%). MS 438 (MH⁺).

Example 104(S)-4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-3-methyl-butoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 104a) as an off-white solid (69%). MS 512 (MH⁺).

Example 104a (S)-ethyl4-amino-5-(2-(4-(3-hydroxypropoxy)-3-methoxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi,P. G. et al. J. Med. Chem. 1999, 42, 5131.) as brown solid (29%). MS 540(MH⁺).

Example 105(S)-4-amino-5-(2-(3,5-dihydroxybenzamido)-3-methylbutoxy)-2-methyl-quinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 105a) as a white solid (72%). MS 440 (MH⁺).

Example 105a (S)-ethyl4-amino-5-(2-(3,5-dihydroxybenzamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 3,5-dihydroxybenzoic acid as brown solid (29%). MS 468(MH⁺).

Example 106(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 106a) as a white solid (81%). MS 466 (MH⁺).

Example 106a (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid asbrown solid (36%). MS 494 (MH⁺).

Example 107(S)-4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 107a) as an off-white solid (76%). MS 466 (MH⁺).

Example 107a (S)-ethyl4-amino-5-(2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-3-methylbutoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from (S)-ethyl4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate(Example 95b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid asbrown solid (29%). MS 494 (MH⁺).

Example 1084-amino-5-((4-(isonicotinamido)cyclohexyl)methoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((4-(isonicotinamido)cyclohexyl)-methoxy)-2-methylquinoline-3-carboxylate(Example 108a) as an off-white solid (43%). ¹H NMR (400 MHz, DMSO-d₆) δ1.52-2.01 (m, 8H), 2.13 (m, 1H), 2.74 (s, 3H), 3.99 (m, 1H), 4.18 (d,J=6.8 Hz, 2H), 7.05 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.66 (t,J=8.4 Hz, 1H), 7.71 (d, J=6.0 Hz, 2H), 8.40 (d, J=6.8 Hz, 1H), 8.71 (d,J=6.0 Hz, 2H), 12.70 (brs, 1H). MS 435 (MH⁺).

Example 108a ethyl4-amino-5-((4-(isonicotinamido)cyclohexyl)-methoxy)-2-methyl-quinoline-3-carboxylate

Prepared as in Example 2a fromN-(4-((3-Amino-2-cyanophenoxy)methyl)cyclohexyl)-isonicotinamide(Example 108b) and ethyl 3-oxobutanoate as a yellow solid (25%). MS 463(MH⁺).

Example 108bN-(4-((3-Amino-2-cyanophenoxy)methyl)cyclohexyl)isonicotinamide

Prepared as in Example 22b fromN-(4-(Hydroxymethyl)cyclohexyl)isonicotinamide (Example 108c) and2-amino-6-fluorobenzonitrile as a colorless oil (6%). MS 351 (MH⁺).

Example 108c N-(4-(Hydroxymethyl)cyclohexyl)isonicotinamide

Prepared as in Example 24a from (4-Aminocyclohexyl)methanol andisonicotinic acid as a yellow oil (100%). MS 235 (MH⁺).

Example 1094-amino-5-((2-methoxycyclohexyl)oxy)-2-methylquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-5-((2-methoxycyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 109a) as a white solid (79%). ¹H NMR (400 MHz, DMSO-d₆) δ1.20-1.68 (m, 6H), 2.16 (m, 2H), 2.78 (s, 3H), 3.34 (s, 3H), 3.58 (m,1H), 4.50 (m, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.67(t, J=8.8 Hz, 1H), 8.92 (brs, 1H), 12.14 (brs, 1H), 12.86 (brs, 1H). MS331 (MH⁺).

Example 109a ethyl4-amino-5-((2-methoxycyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-Amino-6-(2-methoxycyclohexyloxy)benzonitrile (Example 109b) and ethyl3-oxobutanoate as a pale yellow oil (16%). MS 359 (MH⁺).

Example 109b 2-Amino-6-(2-methoxycyclohexyloxy)benzonitrile

Prepared as in Example 22b from 2-methoxycyclohexanol and2-amino-6-fluoro-benzonitrile as a yellow oil (34%). MS 247 (MH⁺).

Example 1104-amino-5-((1-(3-hydroxybenzoyl)piperidin-3-yl)methoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-3-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 110a) as a white solid (35%). MS 436 (MH⁺).

Example 110a ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-3-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-2-methyl-5-(piperidin-3-ylmethoxy)-quinoline-3-carboxylate(Example 110b) and 3-hydroxybenzoic acid as a white solid (34%). MS 464(MH⁺).

Example 110b ethyl4-amino-2-methyl-5-(piperidin-3-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from benzyl3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example110c) and ethyl 3-oxobutanoate as a yellow oil (21%). MS 344 (MH⁺).

Example 110c benzyl3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 24c from2-amino-6-(piperidin-3-ylmethoxy)benzonitrile (Example 110d) as a yellowsolid (70%).

Example 110d 2-amino-6-(piperidin-3-ylmethoxy)benzonitrile

Prepared as in Example 24d from 3-piperidinemethanol and2-amino-6-fluoro-benzo-nitrile as a light yellow solid (27%). MS 232(MH⁺).

Example 1114-amino-5-((1-(3-hydroxybenzoyl)piperidin-2-yl)methoxy)-2-methylquino-line-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 111a) as an off-white solid (35%). ¹H NMR (400 MHz, DMSO-d₆) δ1.25-1.89 (m, 6H), 2.74 (s, 3H), 3.44 (m, 2H), 4.27 (m, 1H), 4.75 (m,2H), 5.29 (m, 1H), 6.64-6.73 (m, 2H), 6.78 (d, J=7.2 Hz, 1H), 7.18 (m,2H), 7.26 (d, J=8.4 Hz, 1H), 7.68 (m, 1H), 8.87 (brs, 1H), 9.73 (brs,1H), 11.96 (brs, 1H), 12.70 (brs, 1H). MS 436 (MH⁺).

Example 111a ethyl4-amino-5-((1-(3-hydroxybenzoyl)piperidin-2-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from ethyl4-amino-2-methyl-5-(piperidin-2-ylmethoxy)-quinoline-3-carboxylate(Example 111b) and 3-hydroxybenzoic acid as a white solid (28%). MS 464(MH⁺).

Example 111b ethyl4-amino-2-methyl-5-(piperidin-2-ylmethoxy)quinoline-3-carboxylate

Prepared as in Example 2a from benzyl2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example111c) and ethyl 3-oxobutanoate as a colorless oil (13%). MS 344 (MH⁺).

Example 111c benzyl2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate

Prepared as in Example 24c from2-amino-6-(piperidin-2-ylmethoxy)benzonitrile (Example 11 id) as ayellow solid (100%). MS 366 (MH⁺).

Example 111d 2-Amino-6-(piperidin-2-ylmethoxy)benzonitrile

Prepared as in Example 24d from 2-piperidinemethanol and2-amino-6-fluoro-benzo-nitrile as a light yellow solid (64%). MS 232(MH⁺).

Example 112 4-amino-5-cyclopropyl-2-methylquinoline-3-carboxylic acid

Prepared as in Example 1 from ethyl4-amino-5-cyclopropyl-2-methylquinoline-3-carboxylate (Example 112a) asa white solid (85%). ¹H NMR (400 MHz, MeOH-d₄) δ 1.03 (m, 2H), 1.31 (m,2H), 2.53 (m, 1H), 2.81 (s, 3H), 7.50 (m, 1H), 7.58 (m, 1H), 7.73 (m,1H). MS 243 (MH⁺).

Example 112a ethyl 4-amino-5-cyclopropyl-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-cyclopropylbenzonitrile(Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl3-oxobutanoate as a pale yellow solid (80%). MS 271 (MH⁺).

Example 1134-amino-2-(carboxymethyl)-5-(2-cyclohexylethyl)quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2-cyclohexylethyl)-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate(Example 113a) as an orange solid (69%). ¹H NMR (400 MHz, DMSO-d₆) δ0.89-0.92 (m, 2H), 1.14-1.29 (m, 4H), 1.44-1.49 (m, 2H), 1.56-1.66 (m,4H), 1.73-1.76 (m, 1H), 3.15 (t, J=8.0 Hz, 2H), 3.70 (s, 2H), 7.09-7.11(m, 1H), 7.38-7.42 (m, 1H), 7.46-7.51 (m, 2H). MS 338 (MH⁺—H₂O).

Example 113a ethyl4-amino-5-(2-cyclohexylethyl)-2-(2-ethoxy-2-oxoethyl)quinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(2-cyclohexylethyl)benzonitrile(Example 113b) and diethyl 3-oxopentanedioate as an orange solid (33%).¹H NMR (400 MHz, DMSO-d₆) δ 0.87-0.96 (m, 2H), 1.14-1.22 (m, 7H),1.27-1.32 (m, 4H), 1.47-1.52 (m, 2H), 1.61-1.68 (m, 4H), 1.74-1.77 (m,2H), 3.21-3.25 (m, 2H), 4.03 (s, 2H), 4.09 (q, J=8.0 Hz, 2H), 4.27 (q,J=8.0 Hz, 2H), 7.27 (t, J=4.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.63(brs, 2H). MS 413 (MH⁺).

Example 113b 2-amino-6-(2-cyclohexylethyl)benzonitrile

Prepared as in Example 21b from2-amino-6-(cyclohexylethynyl)benzonitrile (Example 113c) as an orangesolid (36%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.90-0.95 (m, 2H), 1.16-1.24(m, 4H), 1.41-1.46 (m, 2H), 1.60-1.75 (m, 5H), 2.58-2.62 (m, 2H), 5.90(s, 2H), 6.48 (d, J=8.0 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 7.18 (t, J=4.0Hz, 1H). MS 229 (MH⁺).

Example 113c 2-amino-6-(cyclohexylethynyl)benzonitrile

Prepared as in Example 21c from ethynylcyclohexane and2-amino-6-bromobenzonitrile as a brown oil (100%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.24-1.77 (m, 10H), 2.70 (m, 1H), 6.13 (s, 2H), 6.64 (d,J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H). MS 225(MH⁺).

Example 114 4-amino-5-(3-methoxyphenyl)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-methoxyphenyl)-2-methylquinoline-3-carboxylate (Example114a) as an off-white solid (38%). MS 309 (MH⁺).

Example 114a ethyl4-amino-5-(3-methoxyphenyl)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from3-amino-3′-methoxy-[1,1′-biphenyl]-2-carbonitrile (Example 114b) andethyl 3-oxobutanoate as a pale yellow solid (55%). MS 337 (MH⁺).

Example 114b 3-amino-3′-methoxy-[1,1′-biphenyl]-2-carbonitrile

To a stirred solution of 2-amino-6-bromobenzonitrile (195 mg, 1.0 mmol)and (3-methoxyphenyl)boronic acid (300 mg, 2 mmol) in dioxane (2 mL) wasadded aqueous potassium carbonate (2.0 mmol, 0.7 mL). The reactionsolution was degassed by bubbling N₂ for 2 minutes. Palladiumtetrakistriphenylphosphine (5% mol) was added to the reaction mixtureand the reaction vessel was placed in a microwave reactor and irradiatedat 165° C. for 20 minutes. The precipitate was removed by filtration andthe filtrate concentrated. The residue was purified by HPLC(acetonitrile/water; 10-90% gradient, 25 minutes) to give the titlecompound as an off-white solid (180 mg, 80%). MS 225 (MH⁺).

Example 115 4-amino-5-(cyclohexylmethoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(cyclohexylmethoxy)-2-methylquino-line-3-carboxylate (Example115a) as a white solid (84%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.03-1.29 (m,5H), 1.63-1.82 (m, 5H), 1.94 (m, 1H), 2.75 (s, 3H), 4.06 (d, J=6.4 Hz,2H), 7.03 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.66 (t, J=8.4 Hz,1H). MS 315 (MH⁺).

Example 115a ethyl4-amino-5-(cyclohexylmethoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-(cyclohexylmethoxy)benzonitrile(Example 115b) and ethyl 3-oxobutanoate as a pale yellow solid (47%). ¹HNMR (400 MHz, MeOD) δ 1.12-1.37 (m, 6H), 1.42 (t, J=4.0 Hz, 3H),1.73-2.01 (m, 5H), 2.68 (s, 3H), 4.06 (d, J=4.0 Hz, 2H), 4.42 (q, J=8.0Hz, 2H), 6.96 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0Hz, 1H). MS 343 (MH⁺).

Example 115b 2-amino-6-(cyclohexylmethoxy)benzonitrile

Prepared as in Example 22b from cyclohexylmethanol and2-amino-6-fluorobenzonitrile as a colorless oil (50%). ¹H NMR (400 MHz,CDCl₃) δ 1.07-1.09 (m, 2H), 1.28-1.32 (m, 3H), 1.75-1.90 (m, 6H), 3.79(d, J=6.4 Hz, 2H), 4.37 (s, 2H), 6.20 (d, J=8.4 Hz, 1H), 6.28 (d, J=8.4Hz, 1H), 7.19 (t, J=8.4 Hz, 1H). MS 231 (MH⁺).

Example 116 4-amino-5-(cyclohexylmethoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-phenoxyquinoline-3-carboxylate (Example 116a) as anoff-white solid (47%). ¹H NMR (400 MHz, DMSO-d₆) & 2.77 (s, 3H), 6.60(d, J=4.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.30 (t, J=8.0 Hz, 1H), 7.40(dd, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 2H), 7.60 (t, J=8.0 Hz, 1H), 8.81(brs, 1H), 12.20 (brs, 1H), 12.81 (brs, 1H). MS 295 (MH⁺).

Example 116a ethyl 4-amino-2-methyl-5-phenoxyquinoline-3-carboxylate

Prepared as in Example 2a from 2-amino-6-phenoxybenzonitrile and ethyl3-oxobutanoate as a yellow oil (72%). ¹H NMR (400 MHz, DMSO-d₆) & 1.32(t, J=8.0 Hz, 3H), 2.59 (s, 3H), 4.33 (q, J=8.0 Hz, 2H), 6.61 (dd, J=8.0Hz, 1H), 7.16 (d, J=4.0 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.39-7.52 (m,4H), 7.93 (brs, 2H). MS 323 (MH⁺).

Example 1174-amino-5-(3-((4-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-((4-methoxybenzyl)amino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate(Example 117a) as an off-white solid (38%). MS 438 (MH⁺).

Example 117a ethyl4-amino-5-(3-((4-methoxybenzyl)amino)-2,2-dimethyl-3-oxopro-poxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and (4-methoxyphenyl)methanamine as a yellow solid(100%). MS 466 (MH⁺).

Example 1184-amino-2-methyl-5-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-2-methyl-5-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-3-carboxylate(Example 118a) as an off-white solid (80%). ¹H NMR (400 MHz, DMSO-d₆) δ1.81 (m, 2H), 2.06 (m, 2H), 2.75 (s, 3H), 3.87 (m, 2H), 4.91 (m, 1H),7.15 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H).MS 303 (MH⁺).

Example 118a ethyl4-amino-2-methyl-5-((tetrahydro-2H-pyran-4-yl)oxy)quinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (Example 118b) andethyl 3-oxobutanoate as a pale yellow solid (51%). MS 331 (MH⁺).

Example 118b 2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile

Prepared as in Example 22b from tetrahydro-2H-pyran-4-ol and2-amino-6-fluorobenzo-nitrile as a colorless oil (48%). ¹H NMR (400 MHz,CDCl₃) δ 1.87 (m, 2H), 2.00 (m, 2H), 3.63 (m, 2H), 4.00 (m, 2H), 4.42(s, 2H), 4.58 (m, 1H), 6.23 (d, J=8.4 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H),7.20 (t, J=8.4 Hz, 1H). MS 219 (MH⁺).

Example 1194-amino-5-(2,2-dimethyl-3-oxo-3-((pyridin-4-ylmethyl)amino)propoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-((pyridin-4-ylmethyl)amino)propoxy)-2-methylquinoline-3-carboxylate(Example 119a) as an off-white solid (44%). MS 409 (MH⁺).

Example 119a ethyl4-amino-5-(2,2-dimethyl-3-oxo-3-((pyridin-4-ylmethyl)amino)propoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 24a from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoicacid (Example 47b) and pyridin-4-ylmethanamine as a brown solid (43%).MS 437 (MH⁺).

Example 1204-amino-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methylquinoline-3-carboxylate(Example 120a) as an off-white solid (33%). ¹H NMR (400 MHz, DMSO-d₆) δ0.98 (s, 6H), 2.75 (s, 3H), 3.37 (s, 2H), 3.97 (s, 2H), 5.12 (brs, 1H),7.01 (d, J=8.4 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H),9.27 (brs, 1H), 12.23 (brs, 1H), 12.73 (brs, 1H). MS 305 (MH⁺).

Example 120a ethyl4-amino-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl acetate (Tachdjian, C. etal. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as apale yellow solid (26%). MS 333 (MH⁺).

Example 1214-amino-5-((1-isobutyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((1-isobutyrylpiperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 121a) as a white solid (38%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.99(m, 6H), 1.13-1.23 (m, 2H), 1.78-1.89 (m, 2H), 2.26 (brs, 1H), 2.51 (m,1H), 2.78 (brs, 3H), 2.88 (m, 1H), 3.06 (t, J=12.0 Hz, 1H), 4.02 (d,J=12.0 Hz, 1H), 4.41 (m, 2H), 4.44 (d, J=12.0 Hz, 1H), 7.07 (brs, 1H),7.28 (d, J=8.0 Hz, 1H), 7.70 (brs, 1H), 8.76 (brs, 1H), 12.37 (brs, 1H),12.67 (brs, 1H). MS 386 (MH⁺).

Example 121a ethyl4-amino-5-((1-isobutyrylpiperidin-4-yl)methoxy)-2-methylquino-line-3-carboxylate

Prepared as in Example 2a from2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile(Example 121b) and ethyl 3-oxobutanoate as a yellow oil (36%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.97 (m, 6H), 1.32 (t, J=8.0 Hz, 3H), 1.79-1.88 (m,3H), 2.15-2.18 (m, 2H), 2.55 (s, 3H), 2.86 (m, 1H), 3.04 (m, 1H), 4.00(m, 2H), 4.07 (d, J=4.0 Hz, 2H), 4.32 (q, J=8.0 Hz, 2H), 4.46 (m, 1H),6.91 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H),8.07 (brs, 2H). MS 414 (MH⁺).

Example 121b2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile

Prepared as in Example 22b from1-(4-(hydroxymethyl)piperidin-1-yl)-2-methylpropan-1-one (Example 121c)and 2-amino-6-fluorobenzonitrile as a pale yellow solid (21%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.99 (m, 6H), 1.13-1.24 (m, 2H), 1.74-1.81 (m, 2H),1.99 (m, 1H), 2.55 (m, 1H), 2.84 (m, 1H), 3.01 (m, 1H), 3.88 (m, 2H),4.02 (m, 1H), 4.46 (m, 1H), 5.99 (s, 2H), 6.22 (d, J=8.0 Hz, 1H), 6.34(d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H). MS 302 (MH⁺).

Example 121c 1-(4-(hydroxymethyl)piperidin-1-yl)-2-methylpropan-1-one

Prepared as in Example 24a from isobutyric acid andpiperidin-4-ylmethanol as a colorless oil (36%). MS 186 (MH⁺).

Example 1224-amino-5-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-2-methylquino-line-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-(((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 122a) as a white solid (64%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.70(d, J=6.8 Hz, 3H), 0.89 (t, J=7.6 Hz, 6H), 0.9-1.0 (m, 2H), 1.04 (m,2H), 1.50-1.82 (m, 5H), 1.95-2.05 (m, 1H), 2.05-2.20 (m, 1H), 2.72 (s,3H), 4.52 (t-d, J=10.4, 4.4 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.21 (d,J=8.0 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 8.68 (brs, 1H), 11.72 (brs, 1H),12.73 (brs, 1H). MS 357 (MH⁺).

Example 122a ethyl4-amino-5-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-(((1R,2S,5R)-2-isopropyl-5-methylcyclo-hexyl)oxy)benzonitrile(Example 122b) and ethyl 3-oxobutanoate as a pale yellow solid (43%). MS385 (MH⁺).

Example 122b2-amino-6-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)benzo-nitrile

Prepared as in Example 22b from(1R,2S,5R)-2-isopropyl-5-methylcyclohexanol and2-amino-6-fluorobenzonitrile as a white solid (51%). MS 273 (MH⁺).

Example 1234-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxybenzamido)-2-methylpro-poxy)-2-methylquinoline-3-carboxylicacid hydrochloride

To a stirred suspension of4-amino-5-(2-(3-(2-hydroxyethoxy)-5-methoxybenzamido)-2-methylpropoxy)-2-methylquinoline-3-carboxylicacid (Example 38, 263 mg, 0.544 mmol) in EtOH (2 mL) was added HCl inEtOH (1.25 N, 479 uL, 1.1 equiv.). The mixture was stirred at roomtemperature until it became a clear solution (0.5 h). The solution wasconcentrated under reduced pressure to give the title compound as awhite solid, which was further purified by re-crystallization fromEtOH/H₂O and dried under vacuum overnight (248 mg, 87%). ¹H NMR (400MHz, DMSO-d₆) δ 1.51 (s, 6H), 2.80 (s, 3H), 3.68 (t, J=5.2 Hz, 2H), 3.74(s, 3H), 3.97 (t, J=5.2 Hz, 1H), 4.53 (s, 2H), 6.59 (s, 1H), 6.92 (s,1H), 6.94 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.86(t, J=8.4 Hz, 1H), 8.03 (s, 1H), 9.40 (s, 1H), 9.98 (s, 1H). 484(MH⁺—HCl).

Example 1244-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylic acidhydrochloride

Prepared as in Example 123 from4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylic acid(Example 18) as a white solid (100%). ¹H NMR (400 MHz, DMSO-d₆) δ1.29-1.37 (m, 2H), 1.51-1.66 (m, 4H), 1.82-1.90 (m, 2H), 2.43-2.51 (m,1H), 2.81 (s, 3H), 4.18 (d, J=7.2 Hz, 2H), 7.24 (d, J=8.4 Hz, 1H), 7.60(d, J=8.4 Hz, 1H), 7.84 (t, J=8.4 Hz, 1H), 9.25 (brs, 1H), 9.86 (brs,1H). MS 301 (MH⁺—HCl).

Example 1254-amino-5-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate(Example 125a) as a white solid (23%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.67(brs, 2H), 2.09 (m, 2H), 2.31 (brs, 1H), 2.92 (brs, 2H), 3.48 (brs, 2H),3.82 (s, 3H), 4.15 (brs, 2H), 4.25 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz,2H), 7.14 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz,2H), 7.76 (t, J=8.0 Hz, 1H). MS 436 (MH⁺).

Example 125a ethyl4-amino-5-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile(Example 125b) and ethyl 3-oxobutanoate as an off-white solid (30%). ¹HNMR (400 MHz, DMSO-d₆) δ 1.29-1.33 (m, 5H), 1.74 (m, 2H), 1.92 (m, 3H),2.54 (s, 3H), 2.83 (m, 2H), 3.38 (s, 2H), 3.71 (s, 3H), 4.04 (d, J=8.0Hz, 2H), 4.31 (q, J=8.0 Hz, 2H), 6.86 (d, J=8.0 Hz, 2H), 6.90 (d, J=8.0Hz, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 8.04 (brs, 2H). MS 464 (MH⁺).

Example 125b2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile

Prepared as in Example 22b from(1-(4-methoxybenzyl)piperidin-4-yl)methanol (Example 125c) and2-amino-6-fluorobenzonitrile as an orange solid (19%). MS 352 (MH⁺).

Example 125c (1-(4-methoxybenzyl)piperidin-4-yl)methanol

To a solution of 4-piperidinemethanol (2.28 g, 19.78 mmol) and4-methoxybenzaldehyde (2.30 mL, 19.77 mmol) in THF/DCE (1:1 by volume,100 mL) was added acetic acid (1 mL), followed by NaBH(OAc)₃ (16.76 g,79.08 mmol) in small portions. The reaction mixture was stirred at roomtemperature overnight under N₂. The reaction was diluted with DCM andbasified to pH=10 with 2 N NaOH solution. The organic layer wasseparated, dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified by chromatography on silica gel(Eluent: 60% EtOAc in hexanes) to give the title compound as a paleyellow oil (2.13 g, 46%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.04-1.13 (m, 2H),1.28-1.32 (m, 1H), 1.58-1.61 (m, 2H), 1.79-1.86 (m, 2H), 2.75-2.77 (m,2H), 3.22 (t, J=8.0 Hz, 2H), 3.34 (s, 2H), 3.72 (s, 3H), 4.38 (t, J=4.0Hz, 1H), 6.85 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H). MS 236 (MH⁺).

Example 1264-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)methoxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from ethyl4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)-methoxy)-2-methylquinoline-3-carboxylate(Example 126a) as a yellow solid (76%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.00(d, J=6.8 Hz, 6H), 1.15-2.32 (m, 10H), 2.75 (s, 3H), 3.82 (o, J=7.6 Hz,1H), 4.16 (d, J=6.8 Hz, 2H), 7.07 (br d, J=7.2 Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.67 (br t, 1H), 8.77 (s, 1H), 12.23(s, 1H), 12.66 (s, 1H). MS 400 (MH⁺).

Example 126a ethyl4-amino-5-((4-(isopropylcarbamoyl)cyclohexyl)methoxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from4-((3-amino-2-cyanophenoxy)methyl)-N-isopropyl-cyclohexanecarboxamide(Example 126b) and ethyl 3-oxobutanoate as a pale yellow solid (37%). ¹HNMR (400 MHz, DMSO-d₆) δ 1.01 (d, J=6.4 Hz, 6H), 1.32 (t, J=7.2 Hz, 3H),1.38-1.81 (m, 8H), 1.88 (m, 1H), 2.25 (m, 1H), 2.55 (s, 3H), 3.82 (bro,J=7.6 Hz, 1H), 4.10 (d, J=6.4 Hz, 2H), 4.31 (q, J=7.6 Hz, 2H), 6.93 (d,J=7.6 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.50 (m, 2H), 8.09 (s, 2H). MS428 (MH⁺).

Example 126b4-((3-amino-2-cyanophenoxy)methyl)-N-isopropylcyclohexanecarbox-amide

Prepared as in Example 21b from4-((2-cyano-3-nitrophenoxy)methyl)-N-isoproplycyclo-hexanecarboxamide(Example 126c) as a yellow solid (81%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.99(d, J=5.6 Hz, 6H), 1.22-1.99 (m, 9H), 2.17 (m, 1H), 3.80 (m, 1H), 3.88(d, J=7.2 Hz, 2H), 5.94 (brs, 2H), 6.18 (t, J=8.0 Hz, 1H), 6.23 (d,J=8.0 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 7.44 (s, 1H). MS 316 (H⁺).

Example 126c4-((2-cyano-3-nitrophenoxy)methyl-N-isopropylcyclohexanecarboxamide

To a solution of 4-(hydroxymethyl)-N-isopropylcyclohexanecarboxamide(Example 126d, 480 mg, 2.41 mmol) in dry THF (10 mL) was added NaH (60%in mineral oil, 116 mg, 4.82 mmol) in small portions at 0° C. under N₂.The reaction mixture was stirred at 0° C. under N₂ for 2 h. To thissolution was added 2,6-dinitrobenzonitrile (465 mg, 2.41 mmol), and thereaction mixture was stirred at 0° C.-RT for another 2 h, and then at60° C. overnight under N₂ and cooled down to room temperature. Thereaction was quenched with brine, and extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The residue waspurified by chromatography on silica gel (eluent: 50% EtOAc in hexanes)to give the title compound as yellow solid (594 mg, 71%). ¹H NMR (400MHz, DMSO-d₆) δ 1.00 (d, J=7.6 Hz, 6H), 1.22-2.08 (m, 9H), 2.19 (m, 1H),3.79 (m, 1H), 4.15 (d, J=7.6 Hz, 2H), 7.45 (brs, 1H), 7.78 (d, J=7.2 Hz,1H), 7.88 (m, 2H). MS 346 (H⁺).

Example 126d 4-(hydroxymethyl)-N-isopropylcyclohexanecarboxamide

Prepared as in Example 24a from 4-(hydroxymethyl)cyclohexanecarboxylicacid and propan-2-amine as a colorless oil (57%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.00 (d, J=7.6 Hz, 6H), 1.22-2.08 (m, 9H), 2.12 (m, 1H), 3.28(t, J=7.6 Hz, 2H), 3.79 (m, 1H), 4.34 (s, 1H), 7.43 (s, 1H). MS 200(MH⁺).

Example 127 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylicacid hydrochloride

To a suspension of4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acid (Example36, 1.0 g, 3.33 mmol) in ethanol (10 mL) was added 1.25 M solution ofHCl in ethanol (2.93 mL, 3.66 mmol). The clear solution was stirred for30 minutes and evaporated to dryness to provide4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acidhydrochloride (1.12 g, 100%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 1.30 (m, 1H), 1.39-1.47 (m, 2H), 1.53-1.72 (m, 5H), 2.01-2.05 (m, 2H),2.82 (s, 3H), 4.78-4.82 (m, 1H), 7.29-7.31 (d, J=8.0 Hz, 1H), 7.61-7.63(d, J=8.0 Hz, 1H), 7.82 (t, J=8.4 Hz, 1H), 9.30 (bs, 1H), 9.93 (bs, 1H).MS 301 (MH⁺—HCl).

Example 128 sodium4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate

To a solution of4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acid (Example36, 1.0 g, 3.33 mmol) in ethanol (20 mL) was added a solution of NaHCO₃(294 mg, 3.50 mmol) in water (15 mL). The mixture was stirred and warmedup to 60° C. until the solution become clear then evaporated to drynessto provide sodium4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (1.07 g, 100%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.25-1.45 (m, 3H),1.50-1.70 (m, 5H), 1.53-1.72 (m, 5H), 1.98-2.00 (m, 2H), 2.64 (s, 3H),4.59-4.63 (m, 1H), 6.87-6.89 (d, J=7.6 Hz, 1H), 7.20-7.22 (d, J=8.0 Hz,1H), 7.42 (t, J=8.0 Hz, 1H). MS 301 (MH⁺+H-Na).

Example 129(±)-4-amino-5-((2-(5-(isopropylcarbamoyl)-2-methoxyphenoxy)cyclohexyl)-oxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from (±)-ethyl4-amino-5-((2-(5-(isopropylcarbamoyl)-2-methoxyphenoxy)cyclohexyl)oxy)-2-methylquinoline-3-carboxylate(Example 129a) as a white solid (34%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.15(d, J=8.0 Hz, 6H), 1.35-1.51 (m, 3H), 1.63-1.73 (m, 3H), 2.09 (d, J=12.0Hz, 1H), 2.24 (d, J=12.0 Hz, 1H), 2.72 (s, 3H), 3.56 (s, 3H), 3.99-4.07(m, 1H), 4.71-4.78 (m, 2H), 6.85 (d, J=8.0 Hz, 1H), 7.24 (d, J=12.0 Hz,2H), 7.42 (dd, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.66 (t, J=8.0 Hz,1H), 8.03 (d, J=8.0 Hz, 1H), 8.64 (brs, 1H), 12.00 (brs, 1H), 12.61(brs, 1H). MS 508 (MH⁺).

Example 129a (±)-ethyl4-amino-5-((2-(5-(isopropylcarbamoyl)-2-methoxyphenoxy)-cyclohexyl)oxy)-2-methylquinoline-3-carboxylate

Prepared as in Example 2a from(±)-3-((2-(3-amino-2-cyanophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide(Example 129b) and ethyl 3-oxobutanoate as a yellow solid (78%). MS 536(MH⁺).

Example 129b(±)-3-((2-(3-amino-2-cyanophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide

Prepared as in Example 21b from(±)-3-((2-(2-cyano-3-nitrophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide(Example 129c) as a brown oil (29%). ¹H NMR (400 MHz, DMSO-d₆) δ1.13-1.19 (m, 6H), 1.42-1.66 (m, 6H), 2.02-2.07 (m, 2H), 3.74 (s, 3H),4.08 (m, 1H), 4.47 (m, 1H), 4.57 (m, 1H), 5.93 (brs, 2H), 6.32 (d, J=8.0Hz, 1H), 6.38 (d, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0Hz, 1H), 7.48-7.50 (m, 2H), 7.98 (d, J=8.0 Hz, 1H). MS 424 (MH⁺).

Example 129c(±)-3-((2-(2-cyano-3-nitrophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide

Prepared as in Example 126c from(±)-3-((2-hydroxycyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide (Example129d) and 2,6-dinitrobenzonitrile as a brown solid (100%). MS 454 (MH⁺).

Example 129d(±)-3-((2-hydroxycyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide

Prepared as in Example 24a from(±)-3-((2-hydroxycyclohexyl)oxy)-4-methoxybenzoic acid (Example 129e)and propan-2-amine as a white solid (80%). ¹H NMR (400 MHz, DMSO-d₆) δ1.14 (d, J=8.0 Hz, 6H), 1.25-1.30 (m, 4H), 1.61 (m, 2H), 1.85 (m, 2H),3.56 (m, 1H), 3.79 (s, 3H), 4.03-4.12 (m, 2H), 4.81 (d, J=4.0 Hz, 1H),6.98 (d, J=8.0 Hz, 1H), 7.45-7.49 (m, 2H), 8.01 (d, J=8.0 Hz, 1H). MS308 (MH⁺).

Example 129e (±)-3-((2-hydroxycyclohexyl)oxy)-4-methoxybenzoic acid

Prepared as in Example 1 from (±)-ethyl3-((2-hydroxycyclohexyl)oxy)-4-methoxy-benzoate (Example 129f) as awhite solid (100%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.23-1.25 (m, 4H), 1.59(brs, 2H), 1.88 (m, 2H), 3.53 (m, 1H), 3.72 (s, 3H), 3.92 (m, 1H), 4.73(d, J=4.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 7.39 (dd, J=4.0 Hz, 1H), 7.48(d, J=4.0 Hz, 1H).

Example 129f (±)-ethyl 3-((2-hydroxycyclohexyl)oxy)-4-methoxy-benzoate

To a solution of methyl 3-hydroxy-4-methoxybenzoate (210 mg, 1.15 mmol)and cyclohexane oxide (466 uL, 4.61 mmol) in ethanol (11 mL) was addedK₂CO₃ (637 mg, 4.61 mmol) at room temperature. The reaction mixture wasthen refluxed overnight then cooled down to room temperature, andevaporated under reduced pressure until a small amount of ethanolremained. The solution was diluted with DCM and successively washed with1N HCl and brine, dried over Na₂SO₄ filtered and evaporated underreduced pressure. The residue was purified by chromatography on silicagel (Eluent: 0-20% EtOAc/Hexanes) to afford (±)-ethyl3-((2-hydroxycyclohexyl)oxy)-4-methoxy-benzoate as a colorless oil (307mg, 91%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.16-1.34 (m, 7H), 1.61 (m, 2H),1.84-1.94 (m, 2H), 3.55 (m, 1H), 3.83 (s, 3H), 4.03 (m, 1H), 4.28 (q,J=8.0 Hz, 2H), 4.85 (d, J=4.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H),7.55-7.58 (m, 2H).

Example 1304-amino-5-(cyclohexyloxy)-2-(hydroxymethyl)quinoline-3-carboxylic acid

Prepared as in Example 1 from9-amino-8-(cyclohexyloxy)furo[3,4-b]quinolin-1(3H)-one (Example 130a) asa tan powder (44%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.27-1.46 (m, 2H),1.53-1.71 (m, 6H), 2.00-2.04 (m, 2H), 4.70 (m, 1H), 4.87 (s, 2H), 7.10(d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 8.74(brs, 1H), 11.90 (brs, 1H). MS 317 (MH⁺).

Example 130a 9-amino-8-(cyclohexyloxy)furo[3,4-b]quinolin-1(3H)-one

Prepared as in Example 2a from 2-amino-6-(cyclohexyloxy)benzonitrile(Example 36b) and ethyl 4-chloro-3-oxobutanoate as an orange solid(29%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.30-1.72 (m, 8H), 2.04-2.08 (m, 2H),4.70 (m, 1H), 5.26 (s, 2H), 7.09 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz,1H), 7.64 (m, 2H), 8.14 (brs, 1H). MS 299 (MH⁺).

Example 1311-amino-3-methyl-6b,7,8,9,10,10a-hexahydrobenzofuro[2,3-f]quinoline-2-carboxylicacid

Prepared as in Example 1 from ethyl1-amino-3-methyl-6b,7,8,9,10,10a-hexahydro-benzofuro[2,3-f]quinoline-2-carboxylate(Example 131a) as an off-white solid (28%). ¹H NMR (400 MHz, DMSO-d₆) δ1.35-1.48 (m, 4H), 1.87-1.97 (m, 4H), 2.76 (s, 3H), 3.38 (m 1H), 5.03 (m1H), 7.20 (d, J=8 Hz, 1H), 7.61 (d, J=8 Hz, 1H). MS 299 (MH⁺).

Example 131a ethyl1-amino-3-methyl-6b,7,8,9,10,10a-hexahydrobenzofuro[2,3-f]quinoline-2-carboxylate

Prepared as in Example 2a from2-amino-6-(cyclohex-2-en-1-yloxy)benzonitrile (Example 131b) and ethyl3-oxobutanoate as a pale yellow solid (11%). MS 327 (MH⁺).

Example 131b 2-amino-6-(cyclohex-2-en-1-yloxy)benzonitrile

Prepared as in Example 22b from cyclohex-2-enol and2-amino-6-fluorobenzonitrile as a colorless oil (78%). ¹H NMR (400 MHz,CDCl₃) δ 1.64 (m, 1H), 1.96 (m, 4H), 2.15 (m, 1H), 4.39 (s, 2H), 4.82(m, 1H), 5.87 (m, 1H), 5.98 (m, 1H), 6.30 (d, 2H), 7.20 (t, 1H). MS 215(MH⁺).

Example 132 4-amino-3-carboxy-5-(cyclohexyloxy)-2-methylquinoline1-oxide

Prepared as in Example 1 from4-(N-acetylacetamido)-5-(cyclohexyloxy)-3-(ethoxy-carbonyl)-2-methylquinoline1-oxide (Example 132a) as a white solid (38%). ¹H NMR (400 MHz, DMSO-d₆)δ 1.31-1.68 (m, 8H), 1.98-2.04 (m, 2H), 2.69 (s, 3H), 4.71 (m, 1H), 7.20(d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 8.75(brs, 2H). MS 317 (MH⁺).

Example 132a4-(N-acetylacetamido)-5-(cyclohexyloxy)-3-(ethoxycarbonyl)-2-methyl-quinoline1-oxide

To a solution of ethyl4-(N-acetylacetamido)-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate(Example 132b, 100 mg, 0.24 mmol) in DCE (5 mL) was added mCPBA (163 mg,0.73 mmol). The reaction mixture was stirred at room temperatureovernight under N₂. The solvent was removed under reduce pressure, andthe residue was purified by chromatography on silica gel eluting with0-100% EtOAc/Hexanes gradient to give the title compound as an orangeoil (100 mg, 97%). MS 429 (MH⁺).

Example 132b ethyl4-(N-acetylacetamido)-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate

To a solution of ethyl4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (Example 36a,700 mg, 2.13 mmol) and Et₃N (891 uL, 6.39 mmol) in DCM (20 mL) was addedacetyl chloride (455 uL, 6.39 mmol) at 0° C., and the reaction mixturewas stirred at 0° C.-RT overnight. The reaction was diluted with DCM andwashed successively with 10% citric acid, saturated NaHCO₃, H₂O, andbrine, dried over Na₂SO₄, filtered and evaporated under reducedpressure. The residue was purified by chromatography on silica geleluting with 0-40% EtOAc/Hexanes gradient to afford the title compoundas a yellow oil (100 mg, 11%). MS 413 (MH⁺).

Example 1334-amino-5-((2,3-dihydroxycyclohexyl)oxy)-2-methylquinoline-3-carboxylicacid

Prepared as in Example 1 from3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)cyclohexane-1,2-diyldiacetate (Example 133a) as a white solid (74%). ¹H NMR (400 MHz,DMSO-d₆) δ 1.42-1.50 (m, 3H), 1.66-1.70 (m, 2H), 2.12-2.15 (m, 1H), 2.74(s, 3H), 3.71-3.73 (m, 1H), 3.90 (s, 1H), 4.60-4.62 (m, 1H), 4.71 (brs,1H), 5.18 (brs, 1H), 7.06 (d, J=8 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 7.60(t, J=8.4 Hz, 1H). MS 333 (MH⁺).

Example 133a3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)cyclohexane-1,2-diyldiacetate

Prepared as in Example 2a from3-(3-amino-2-cyanophenoxy)cyclohexane-1,2-diyl diacetate (Example 133b)and ethyl 3-oxobutanoate as a pale yellow solid (32%). MS 445 (MH⁺).

Example 133b 3-(3-amino-2-cyanophenoxy)cyclohexane-1,2-diyl diacetate

Prepared as in Example 21b from3-(2-cyano-3-nitrophenoxy)cyclohexane-1,2-diyl diacetate (Example 133c)as a white solid (84%). MS 333 (MH⁺).

Example 133c 3-(2-cyano-3-nitrophenoxy)cyclohexane-1,2-diyl diacetate

Prepared as in Example 132b from2-((2,3-dihydroxycyclohexyl)oxy)-6-nitrobenzonitrile (Example 133d) andacetyl chloride as a white solid (19%). MS 363 (MH⁺).

Example 133d 2-((2,3-dihydroxycyclohexyl)oxy)-6-nitrobenzonitrile

To a solution of 2-(cyclohex-2-en-1-yloxy)-6-nitrobenzonitrile (Example133e, 5.3 g, 21.7 mmol) in THF/H₂O (1:1 by volume, 110 mL) was addedOsO₄ (110.3 mg, 0.434 mmol) at room temperature. After it was stirredfor 30 minutes, NaClO₃ (2.71 g, 26.04 mmol) was added in small portionsover a period of 1 h, and the reaction mixture was stirred at roomtemperature for 48 h. The reaction was carefully quenched with aqueoussodium bisulfite solution, and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andevaporated. The residue was purified by chromatography on silica geleluting with 80-100% EtOAc in hexanes to give the title compound as abrown solid (3.88 g, 64%). MS 279 (MH⁺).

Example 133e 2-(cyclohex-2-en-1-yloxy)-6-nitrobenzonitrile

Prepared as in Example 126c from cyclohex-2-enol and2,6-dinitrobenzonitrile as a brown solid (90%). MS 245 (MH⁺).

Biological Tests Experiment 1 Screening for Sweet Enhancers

hT1R2/R3-HEK293 Ga15 cells were seeded in 384-well-clear bottom plates(Fisher) at a density of ˜32,000 cells/well and grown overnight. On theday of the experiment, hT1R2/R3-HEK293 Ga15 were loaded with the calciumindicator Fluo3AM (4 mM) (Invitrogen, Carlsbad, Calif.) in D-PBS(Invitrogen, Carlsbad, Calif.) using a Multidrop. Cells were incubatedfor 1 hour at room temperature and excess dye was washed out with D-PBSusing an EMBLA cell washer (Molecular Devices, Sunnyvale, Calif.),leaving a residual volume of 25 ml/well. Sweeteners and test compoundswere prepared at 4× final concentration and mixed 1:1 in a 384-wellGreiner plate (bringing the sweeteners and test compounds concentrationsdown to 2× final concentration). After 30 minutes of rest time at roomtemperature, Fluo3AM-loaded cell plates, and the sweetener/compoundplate mixture were loaded into a Fluorometric Imaging Plate Reader(FLIPR) (Molecular Devices, Sunnyvale, Calif.). Imaging was performedusing a 480 nm excitation and a 535 emission and was initiated with theacquisition of the baseline fluorescence for a period of 7 seconds.Then, the cells were stimulated on line with addition of 25 mlstimuli/well. Subsequent images were acquired every other second for aperiod of 2 minutes. Raw fluorescence counts were then normalized ineach well (using custom made data import software) by calculating deltaF/f values (maximum fluorescent count obtained after stimulation—minimalfluorescent count obtained before stimulation/minimal fluorescent countobtained before stimulation). EC₅₀s were determined using a non-linearregression algorithm (GraphPad PRISM, San Diego, Calif.), where the Hillslope, bottom asymptotes and top asymptotes were allow to vary.Enhancement properties of test compounds were quantified by determiningthe magnitude of the leftward shift in the sweeteners EC₅₀ values (or anEC₅₀ ratio): the value of the EC₅₀ measured in the absence of theenhancer divided by the value of the EC₅₀ measured in the presence ofthe enhancer). The present compounds have been tested and shown sweettaste enhancing activities for sucrose as shown in Table A, Table B andC below. Specifically, the EC50 ratio of the test compounds for sucroseenhancement are all greater than about 2 at about 50 μM. The compoundslisted in Table A, Table B and C below are Examples described above. Forexample, Compound Q in Table A is Example 7.

TABLE A Compound EC₅₀ Ratio (50 μM) J 7.5 C 37.5 E 15.5 S 1.8 U 1.6 K6.9 Q 3.4 I 9.7 N 5.1 O 5 T 1.7 L 6.7 F 13.6 M 5.7 H 9.9 D 21.5 P 4.2 A43.6 (3 μM) B 37.9 R 2.5 G 10.7

TABLE B Compound EC₅₀ Ratio (50 μM) Compound EC₅₀ Ratio (50 μM) V 21.5E2 9.7 A1 10.2 E3 15.8 O1 25.2 H1 3.7 H3 60.4 W2 21.1 P1 45.9 U3 15.9 B122.8 L3 17.3 W 73.8 B3 9.9 I3 317.1 V1 21.6 K3 29.8 I1 4.7 C4 14.6 J113.7 R1 55.8 B2 7.7 D4 23.5 P2 24.7 Q1 45.2 C3 17.6 X 32.5 F4 23.7 C148.4 D3 173.0 E4 176.7 G4 49.2 R3 16.7 M3 13.1 J3 28.6 V2 20.4 G3 40.8V3 51.0 B4 111.7 G2 6.7 Y2 23.3 W1 4.5 M2 13.4 K1 6.7 D1 19.7 F2 3.8 Y21.7 X3 3.6 Z 6.4 N3 3.4 N2 25.7 W3 5.7 Q2 4.4 Q3 17.1 L1 6.4 T1 12.9 H23.2 E1 21.1 U2 93.8 S1 49.0 I2 6.0 L2 31.7 Z3 33.6 F3 5.2 X1 83.1 A388.3 M1 37.0 Z2 34.6 N1 56.7 F1 27.0 Y3 24.5 K2 63.1 A4 86.6 D2 21.2 P39.9 T3 23.9 R2 22.0 X2 55.5 Z1 50.9 J2 13.7 A2 21.9 G1 3.9 Y1 108.9 U18.1 T2 6.2 C2 19.1 O3 5.9 O2 11.3 S2 3.8

TABLE C Sucrose EC₅₀ Ratio Compound (50 μM) L4 27.8 C5 23.8 M4 2.9 I40.9 B5 72.7 W4 6.0 K4 13.7 N4 3.4 X4 4.9 O4 23.0 J4 9.2 V4 27.9 Y4 103.2P4 37.5 R4 9.3 H4 3.1 S4 5.6 Q4 17.4 T4 23.7

The present compounds have been tested and shown sweet taste enhancingactivities for sucralose as shown in Table D below. Specifically, theEC50 ratio of the test compounds for sucralose enhancement are allgreater than about 2 at about 10 μM.

TABLE D Sucralose Sucralose Sucralose EC₅₀ Ratio EC₅₀ Ratio Com- EC₅₀Ratio Compound (10 μM) Compound (10 μM) pound (10 μM) C 2.0 T1 3.6 M34.3 D 4.0 E1 4.2 V2 3.1 A 17.0 S1 5.2 V3 5.9 B 2.5 L2 4.1 K1 2.0 G 2.2F3 1.4 F2 2.2 V 6.7 A3 10.9 W3 2.1 A1 3.4 Z2 10.8 U2 5.0 O1 2.6 F1 4.3Z3 3.1 H3 12.5 K2 7.6 X1 7.7 P1 12.9 D2 2.9 M1 3.1 B1 4.2 T3 3.4 N1 4.4W 9.9 X2 9.3 Y3 2.9 I3 12.9 J2 3.6 A4 6.0 K3 8.4 U1 2.0 P3 2.2 C4 6.0 C23.7 R2 3.4 R1 16.5 O2 2.8 Z1 3.6 D4 1.4 E2 4.0 A2 2.2 Q1 13.4 E3 3.4 Y119.1 X 5.9 H1 1.6 T2 2.4 C1 18.1 W2 5.7 L4 3.4 E4 10.7 U3 4.5 I4 6.8 R35.1 L3 7.2 B5 6.8 J3 5.9 B3 2.9 K4 3.4 G3 23.8 V1 6.1 O4 7.6 B4 8.0 I16.1 J4 2.2 Y2 2.6 J1 4.3 V4 6.0 M2 5.4 B2 3.6 Y4 10.3 D1 8.3 P2 3.4 U48.3 Y 4.6 C3 3.2 P4 11.4 N2 7.2 F4 4.1 S4 1.9 S3 6.8 D3 11.0 Q4 2.5 Q34.0 G4 7.5 T4 3.2

Experiment 2 Sweet Flavor and Sweet Flavor Enhancement Measurement UsingHuman Panelists Conducting a Scaling Test

Test samples containing experimental compounds were compared to adose-response curve for perceived sweetness intensity of sweeteners(sucralose, sucrose, fructose and other sweeteners) concentrations todetermine equivalent sweetness intensity.

A group of eight or more panelists tasted solutions including sweetenersat various concentrations, as well as the experimental compound bothwith and without added sweetener. Panelists then rated sweetnessintensity of all samples on a structured horizontal line scale, anchoredfrom 0 to 15, where 0 equals no sweetness and 15 equals equivalentsweetness to a 15% sucrose sample. Scores for sweetness intensity wereaveraged across panelists. Then using the average scores and/or equationof the line for the sweetener dose-response curve, equivalent sweetnessconcentrations were determined for the samples containing experimentalcompounds.

Subjects had been previously familiarized with the key attribute tasteand were trained to use the 0 to 15 point line scale. Subjects refrainedfrom eating or drinking (except water) for at least 1 hour prior to thetest. Subjects ate a cracker and rinsed with water several times toclean the mouth.

Sweetener solutions are provided at a wide range of concentrations suchas 100 ppm, 200 ppm, 300 ppm, 400 ppm, and 500 ppm for sucralose, orbetween 0% and 12% for sucrose or fructose, in order to create adose-response curve. Samples containing experimental compound wereprepared both alone and in a 100 ppm sucralose solution or a 6% sucroseor fructose solution. All samples were made up in low sodium buffer pH7.1. In order to aid dispersion, solutions can be made up in 0.1%ethanol.

The solutions were dispensed in 20 ml volumes into 1 oz. sample cups andserved to the subjects at room temperature. All samples were presentedin randomized counterbalanced order to reduce response bias. Further,two sessions of testing may be used to check panel precision.

Subjects tasted each sample individually and rate sweetness intensity onthe line scale prior to tasting the next sample. All samples wereexpectorated. Subjects may retaste the samples but can only use thevolume of sample given. Subjects must rinse with water between samples.Eating an unsalted cracker between samples may be required depending onthe samples tasted.

The scores for each sample were averaged across subjects and standarderror was calculated. The dose-response curve was plotted graphically,and this may be used to ensure the panel is rating accurately; i.e.,increasing the concentration of sucralose should correspond to increasedaverage scores for sweetness. A 2-way ANOVA (factors being samples andpanelists) and multiple comparison tests (such as Tukey's HonestlySignificant Difference test) can be used to determine differences amongsamples and/or panelists. A 3-way ANOVA, with sessions as the thirdfactor, can be used to determine if there is any difference in theratings between sessions.

The results of human taste tests with Compound J are found below.Compound J is one of the examples described above. Table 1 indicatesthat 45 μM Compound J in 6% sucrose has sweetness equivalent to about9-10% sucrose.

TABLE 1 AVERAGE SWEETNESS, N = 28 (14 PANELISTS × 2 REP). TUKEY'S VALUE= 0.986 (α = 0.05). Treatment Average SD St Er Tukey (5%) 6% Sucrose 6.61.1 0.2 a 8% Sucrose 8.2 1.1 0.2 b 9% Sucrose 9.2 0.9 0.2 bc 6%Sucrose + 45 uM Compound J 9.4 1.9 0.4 c 10% Sucrose 9.7 1.7 0.3 c 12%Sucrose 10.9 1.5 0.3 d

The results of human taste tests with Compound C are found below.Compound C is one of the examples described above. Table 1_1 indicatesthat 25 μM Compound C in 6% sucrose has sweetness equivalent to about9-10% sucrose.

TABLE 1_1 AVERAGE SWEETNESS, N = 24 (12 PANELISTS × 2 REP). TUKEY'SVALUE = 0.912 (α = 0.05). Treatment Average SD St Er Tukey (5%) 6%Sucrose 6.5 1.1 0.2 a 8% Sucrose 8.2 0.7 0.1 b 9% Sucrose 8.4 1.8 0.4 b6% Sucrose + 25 uM Compound C 9.1 1.0 0.2 bc 10% Sucrose 9.5 0.7 0.1 c

The results of human taste tests with Compound 01 are found below.Compound O1 is one of the examples described above. Table 1_2 indicatesthat 25 μM Compound O1 in 6% sucrose has sweetness equivalent to about10% sucrose.

TABLE 1_2 AVERAGE SWEETNESS, N = 26 (13 PANELISTS × 2 REP). TUKEY'SVALUE = 0.733 (α = 0.05). Treatment Average SD St Er Tukey (5%) 6%Sucrose 6.3 0.7 0.1 a 8% Sucrose 8.2 1.0 0.2 b 9% Sucrose 8.6 1.1 0.2 bc10% Sucrose 9.2 1.0 0.2 c 6% Sucrose + 25 uM Compound O1 9.2 1.1 0.2 c

The results of human taste tests with Compound W are found below.Compound W is one of the examples described above. Table 1_3 indicatesthat 25 μM Compound W in 6% sucrose has sweetness equivalent to about10% sucrose.

TABLE 1_3 AVERAGE SWEETNESS, N = 28 (14 PANELISTS × 2 REP). TUKEY'SVALUE = 0.619 (α = 0.05). Treatment Average SD St Er Tukey (5%) 6%Sucrose 6.2 0.5 0.1 a 8% Sucrose 8.1 1.0 0.2 b 9% Sucrose 8.5 0.9 0.2 b6% Sucrose + 25 uM Compound W 9.2 0.9 0.2 c 10% Sucrose 9.5 1.0 0.2 c

The results of human taste tests with Compound 13 are found below.Compound I3 is one of the examples described above. Table 1_4 indicatesthat 21 μM Compound I3 in 6% sucrose has sweetness equivalent to about10% sucrose.

TABLE 1_4 AVERAGE SWEETNESS, N = 28 (14 PANELISTS × 2 REP). TUKEY'SVALUE = 0.785 (α = 0.05). Treatment Average SD St Er Tukey (5%)  6%Sucrose 6.1 0.4 0.1 a  8% Sucrose 7.8 0.9 0.2 b  9% Sucrose 8.6 1.0 0.2c 10% Sucrose 9.0 0.9 0.2 cd  6% Sucrose + 21 uM Compound I3 9.5 1.0 0.2d

The results of human taste tests with Compound C1 are found below.Compound C1 is one of the examples described above. Table 1_5 indicatesthat 13 μM Compound C1 in 6% sucrose has sweetness equivalent to about10% sucrose and that 33 μM Compound C1 in 6% sucrose has sweetnessequivalent to about 12% sucrose. Table 1_6 indicates that 33 μM CompoundC1 in 50 ppm sucralose has sweetness equivalent to about between 100 ppmsucralose and 200 ppm sucralose.

TABLE 1_5 AVERAGE SWEETNESS, N = 26 (13 PANELISTS × 2 REP). TUKEY'SVALUE = 1.311 (α = 0.05). Treatment Average SD St Er Tukey (5%)  6%Sucrose 6.4 0.7 0.1 a  8% Sucrose 7.9 1.7 0.3 b 10% Sucrose 9.6 1.5 0.3c  6% Sucrose + 13 uM Compound C1 9.6 1.7 0.3 c 12% Sucrose 10.9 1.4 0.3cd  6% Sucrose + 33 uM Compound C1 11.0 1.7 0.3 d

TABLE 1_6 AVERAGE SWEETNESS, N = 30 (15 PANELISTS × 2 REP). TUKEY'SVALUE = 0.911 (α = 0.05). Treatment Average SD St Er Tukey (5%)  50 ppmsucralose 3.9 1.1 0.2 a 100 ppm sucralose 5.9 1.6 0.3 b 50 ppmsucralose + 33 uM 7.5 2.4 0.4 c Compound C1 200 ppm sucralose 8.7 1.80.3 d 300 ppm sucralose 10.2 1.7 0.3 e

The results of human taste tests with Compound B4 are found below.Compound B4 is one of the examples described above. Table 1_7 indicatesthat 36.5 μM Compound B4 in 6% sucrose has sweetness equivalent to about10-12% sucrose. Table 1_8 indicates that 36.5 μM Compound B4 in 50 ppmsucralose has sweetness equivalent to about 100 ppm.

TABLE 1_7 AVERAGE SWEETNESS, N = 27 (14 PANELISTS × 1 REP & 13 PANELISTS× 1 REP). TUKEY'S VALUE = 1.138 (α = 0.05). Tukey Treatment Average SDSt Er (5%)  6% Sucrose 6.6 1.3 0.2 a  8% Sucrose 8.4 1.5 0.3 b 10%Sucrose 10.3 1.2 0.2 c  6% Sucrose + 36.4 uM Compound B4 10.5 1.4 0.3 c12% Sucrose 10.9 1.2 0.3 c

TABLE 1_8 AVERAGE SWEETNESS, N = 26 (13 PANELISTS × 2 REP). TUKEY'SVALUE = 0.985 (α = 0.05). Treatment Average SD St Er Tukey (5%)  50 ppmsucralose 3.9 0.6 0.1 a 100 ppm sucralose 5.5 1.1 0.2 b 50 ppmsucralose + 36.5 uM 6.2 2.0 0.4 b Compound B4 200 ppm sucralose 9.1 1.90.4 c 300 ppm sucralose 10.2 1.8 0.4 d

Experiment 3 Sweet Flavor and Sweet Flavor Enhancement Measurement UsingHuman Panelists Conducting a Paired Comparison Test

Test samples containing experimental compounds are presented in pairs tothe panelist and they are asked to determine which of the sample issweeter. A group of 10-16 or more panelists participated in each test.Subjects refrained from eating or drinking (except water) for at least 1hour prior to the test. Subjects rinsed with water several times toclean the mouth.

All samples are prepared with ethanol to ensure dispersion of thecompound in solution. This includes samples without compound; allsolutions are balanced for 0.1% ethanol.

Samples are also prepared with low sodium buffer (pH 7.1) in place ofwater. Buffer contains 0.952 g of KCl, 5.444 g of Na₂HPO₄, and 0.952 gof KH₂PO₄ in 40 L of DIUF water. Sample volumes are usually 20 ml.

In one paired comparison test, the panelist is presented with twodifferent samples and asked to identify the sample which is sweeter. Thesamples within a paired comparison test are presented in a randomized,counterbalanced order. Panelists have up to a 1 minute delay betweentaste tests to clear the mouth of any tastes.

Binomial probability tables are used to determine the probability of thecorrect number of responses occurring for each test at alpha=0.05

The results of human taste tests with Compound J are found below. Table2 indicates that panelists perceived 6% sucrose+45 uM Compound J asbeing not significantly different in sweetness than a solution of 10%sucrose (p>0.05). Table 3 indicates that 45 μM Compound J alone haslittle or no sweetness on its own.

TABLE 2 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 42 (14 PANELISTS ×3 REP). Samples Total 10% Sucrose 17 6% Sucrose + 45 uM Compound J 25Total 42 6% Sucrose + 45 uM Compound J (p-value) 0.360

TABLE 3 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 48 (16 PANELISTS ×3 REP). Samples Total 1% Sucrose 47 LSB + 45 uM Compound J 1 Total 48LSB + 45 uM Compound J (p-value) <0.001

The results of human taste tests with Compound A are found below. Table2_1 indicates that panelists perceived 6% sucrose+25 uM Compound A asbeing not significantly different in sweetness than a solution of 10%sucrose (p>0.05). Table 3_1 indicates that 25 μM Compound A alone haslittle or no sweetness on its own.

TABLE 2_1 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 16 (16 PANELISTS× 3 REP). Samples Total 10% sucrose 28 6% sucrose + 25 uM Compound A 20Total 48 10% sucrose (p-value) 0.312

TABLE 3_1 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 15 (15 PANELISTS× 3 REP). Samples Total 1% sucrose 44 LSB + 25 uM Compound A 1 Total 451% sucrose (p-value) <0.001

The results of human taste tests with Compound C1 are found below. Table2_2 indicates that panelists perceived 6% sucrose+33 uM Compound C1 asbeing not significantly different in sweetness than a solution of 12%sucrose (p>0.05). Table 3_2 indicates that 33 μM Compound C1 alone haslittle or no sweetness on its own.

TABLE 2_2 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 30 (15 PANELISTS× 2 REPS). Samples Total 12% Sucrose 17 6% Sucrose + 33 uM Compound C113 Total 30 12% Sucrose (p-value) 0.585

TABLE 3_2 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 22 (11 PANELISTS× 2 REPS). Samples Total 1% Sucrose 18 LSB + 33 uM Compound C1 4 Total22 1% Sucrose selected (p-value) 0.004

The results of human taste tests with Compound I3 are found below. Table2_3 indicates that panelists perceived 6% sucrose+25 uM Compound I3 asbeing not significantly different in sweetness than a solution of 12%sucrose (p>0.05). Table 3_3 indicates that 25 μM Compound I3 alone haslittle or no sweetness on its own.

TABLE 2_3 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 42 (14 PANELISTS× 3 REPS). Samples Total 12% Sucrose 18 6% Sucrose + 25 uM Compound I324 Total 42 12% Sucrose (p-value) 0.441

TABLE 3_3 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 42 (14 PANELISTS× 3 REPS). Samples Total 1% Sucrose 36 LSB + 25 uM Compound I3 6 gTotal42 1% Sucrose selected (p-value) <0.001

The results of human taste tests with Compound B4 are found below. Table2_4 indicates that panelists perceived 6% sucrose+36.5 uM Compound B4 asbeing not significantly different in sweetness than a solution of 10%sucrose (p>0.05). Table 3_4 indicates that 36.5 μM Compound B4 alone haslittle or no sweetness on its own.

TABLE 2_4 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 26 (13 PANELISTS× 2 REPS). Samples Total 10% Sucrose 10 6% Sucrose + 36.5 uM Compound B416 Total 26 6% Sucrose + 36.5 uM Compound B4 0.327 (p-value)

TABLE 3_4 SAMPLE SELECTED AS SWEETER BY PANELISTS, N = 45 (15 PANELISTS× 3 REPS). Samples Total 1% Sucrose 44 LSB + 36.5 uM Compound B4 1gTotal 45 1% Sucrose selected (p-value) 0.001

All publications and patent applications herein are incorporated byreference to the same extent as if each individual publication or patentapplication was specifically and individually indicated to beincorporated by reference.

The foregoing detailed description has been given for clearness ofunderstanding only and no unnecessary limitations should be understoodtherefrom as modifications will be obvious to those skilled in the art.It is not an admission that any of the information provided herein isprior art or relevant to the presently claimed inventions, or that anypublication specifically or implicitly referenced is prior art.

Embodiments of this invention are described herein, including the bestmode known to the inventors for carrying out the invention. Variationsof those preferred embodiments may become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorsexpect skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the invention unless otherwise indicatedherein or otherwise clearly contradicted by context.

We claim:
 1. (canceled)
 2. A compound selected from the group consistingof:

or a tautomer, and/or salt thereof.
 3. An ingestible compositioncomprising a compound of claim 2, or a tautomer or salt thereof and aningestibly acceptable excipient.
 4. The ingestible composition of claim3, further comprising one or more sweeteners.
 5. The ingestiblecomposition of claim 4, wherein the sweetener is selected form the groupconsisting of sucrose, fructose, glucose, galactose, mannose, lactose,tagatose, maltose, corn syrup, D-tryptophan, glycine, erythritol,isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, maltitol,isomalt, hydrogenated glucose syrup (HGS), hydrogenated starchhydrolyzate (HSH), stevioside, rebaudioside A, other sweet Stevia-basedglycosides, carrelame, other guanidine-based sweeteners, saccharin,acesulfame-K, cyclamate, sucralose, alitame, mogroside, neotame,aspartame, other aspartame derivatives, and combinations thereof.
 6. Theingestible composition of claim 3, which has an increased sweet taste ascompared to the ingestible composition not containing a compound ofclaim 2, as judged by a majority of a panel of at least eight humantaste testers.
 7. The ingestible composition of claim 3, which is inform of a food or beverage product, a pharmaceutical composition, anutritional product, a dietary supplement, over-the-counter medication,or oral care product.
 8. The ingestible composition of claim 7, whereinthe food or beverage product is for human or animal consumption.
 9. Theingestible composition of claim 7, wherein the food or beverage productis selected from the group consisting of the Soup category; the DriedProcessed Food category; the Beverage category; the Ready Meal category;the Canned or Preserved Food category; the Frozen Processed Foodcategory; the Chilled Processed Food category; the Snack Food category;the Baked Goods category; the Confectionary category; the Dairy Productcategory; the Ice Cream category; the Meal Replacement category; thePasta and Noodle category; the Sauces, Dressings, Condiments category;the Baby Food category; the Spreads category; sweet coatings, frostings,or glazes; and combinations thereof.
 10. A method of enhancing the sweettaste of an ingestible composition comprising contacting the ingestiblecomposition thereof with a compound of claim 2, or a tautomer, and/orsalt thereof, to form a modified ingestible composition.
 11. A sweetenhancing composition, comprising a compound of claim 2, or a tautomer,and/or salt thereof, in an amount effective to provide sweetening incombination with a first amount of sweetener, wherein the sweetening ismore than the sweetening provided by the first amount of sweetenerwithout the compound.
 12. An ingestible composition comprising the sweetenhancing composition of claim
 11. 13. The ingestible composition ofclaim 12, which is in form of a food or beverage product, apharmaceutical composition, a nutritional product, a dietary supplement,over-the-counter medication, or oral care product.
 14. A flavoringconcentrate formulation comprising: i) as flavor modifying ingredient, acompound of claim 2, or a tautomer, and/or salt thereof; ii) a carrier;and iii) optionally at least one adjuvant.
 15. The flavoring concentrateformulation of claim 14, wherein the at least one adjuvant comprises oneor more flavoring agents.
 16. The flavoring concentrate formulation ofclaim 15, wherein the at least one adjuvant comprises one or moresweeteners.
 17. The flavoring concentrate formulation of claim 16,wherein the at least one adjuvant comprises one or more ingredientsselected from the group consisting of a emulsifier, a stabilizer, anantimicrobial preservative, an antioxidant, vitamins, minerals, fats,starches, protein concentrates and isolates, salts, a freezing pointdepressant, nucleating agent, and combinations thereof.
 18. Theflavoring concentrate formulation of claim 17, which is in a formselected from the group consisting of liquid, solid, semi-solid, foamymaterial, paste, gel, cream, lotion, and combinations thereof.
 19. Theflavoring concentrate formulation of claim 18, wherein the compound ofclaim 2 is in a concentration that is at least 2 times of theconcentration in a ready-to-use composition.
 20. A compound of claim 2,selected from the group consisting of:

or a tautomer, and/or a salt thereof.
 21. A compound of claim 2,selected from the group consisting of:

or a tautomer, and/or salt thereof.
 22. A compound of claim 2, selectedfrom the group consisting of:

or a tautomer, and/or salt thereof.
 23. A compound of claim 2, selectedfrom the group consisting of:

or a tautomer, and/or salt thereof.
 24. A compound of claim 2, selectedfrom the group consisting of:

or a tautomer, and/or a salt thereof.
 25. A compound of claim 2,selected from the group consisting of:

or a tautomer, and/or a salt thereof.